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We measured annual prevalence of microbiologically defined nontuberculous mycobacterial lung disease in Ontario, Canada. Mycobacterium avium prevalence was 13 cases/100,000 persons in 2020, a 2.5-fold increase from 2010, indicating a large increase in true M. avium lung disease. During the same period, M. xenopi decreased nearly 50%, to 0.84 cases/100,000 persons. [ABSTRACT FROM AUTHOR]

Objective: This paper provides an overview of financing for tuberculosis (TB) prevention, diagnostic and treatment services in the World Health Organization (WHO) Western Pacific Region during 2005-2020. Methods: This analysis uses the WHO global TB finance database to describe TB funding during 2005-2020 in 18 low- and middle-income countries (LMICs) in the Western Pacific Region, with additional country-level data and analysis for seven priority countries: Cambodia, China, the Lao People's Democratic Republic, Mongolia, Papua New Guinea, the Philippines and Viet Nam. Results: Funding for the provision of TB prevention, diagnostic and treatment services in the 18 LMICs tripled from US$ 358 million in 2005 to US$ 1061 million in 2020, driven largely by increases in domestic funding, which rose from US$ 325 million to US$ 939 million over the same period. In the seven priority countries, TB investments also tripled, from US$ 340 million in 2005 to US$ 1020 million in 2020. China alone accounted for much of this growth, increasing its financing for TB programmes and services five-fold, from US$ 160 million to US$ 784 million. The latest country forecasts estimate that US$ 3.8 billion will be required to fight TB in the seven priority countries by 2025, which means that unless additional funding is mobilized, the funding gap will increase from US$ 326 million in 2020 to US$ 830 million by 2025. Discussion: Increases in domestic funding over the past 15 years reflect a firm political commitment to ending TB. However, current funding levels do not meet the required needs to finance the national TB strategic plans in the priority countries. An urgent step-up of public financing efforts is required to reduce the burden of TB in the Western Pacific Region. [ABSTRACT FROM AUTHOR]

The mechanisms underlying host resistance to Mycobacterium avium subsp. paratuberculosis (MAP) infection are largely unknown. In the current study, we hypothesize that cows with an ability to produce higher levels of interferon-gamma (IFNɣ) might control MAP infection more successfully. To test this hypothesis, IFNɣ production was measured using a specific IFNɣ ELISA kit in avian purified protein derivative (aPPD)-stimulated blood samples collected from 152 Holstein cattle. DNA isolated from peripheral blood samples of the animals included in the study was genotyped with the EuroG Medium-Density Bead Chip, and the genotypes were imputed to whole-genome sequencing. A genome-wide association analysis (GWAS) revealed that high levels of IFNɣ in response to the aPPD were associated with a specific genetic profile (heritability = 0.64) and allowed the identification of 71 SNPs, 40 quantitative trait loci (QTL), and 104 candidate genes. A functional analysis using the 104 candidate genes revealed a significant enrichment of genes involved in the innate immune response and, more specifically, in necroptosis. Taken together, our results define a heritable and distinct immunogenetic profile associated with the production of high IFNɣ levels and with the capacity of the host to lyse MAP-infected macrophages by necroptosis. [ABSTRACT FROM AUTHOR]

Mycobacterium avium complex (MAC) houses a group of non-tuberculous mycobacteria causing pulmonary and disseminated infections. They are accountable for nodular bronchiectatic and fibrocavitary lung diseases in humans, Johne’s disease in ruminants, and respiratory diseases in birds. MAC infections pose challenges, owing to antibiotic resistance, prolonged therapy with antibiotic combinations, side effects, and risk of reinfections. Our objective was to summarize the outcome of computational research on the bacteria in MAC. This aimed to advance our understanding of characteristics, pathogenicity, and transmission dynamics to control infections. We incorporated information from the research on genomes, microbiomes, phylogeny, transcriptomes, proteomes, antibiotic resistance, and vaccine/drug target development to enhance our knowledge. It illuminated the significance of computational studies in distinguishing MAC species/subspecies and recognizing: virulence factors, lineage-specific markers, and transmission clusters. Moreover, it assisted in understanding: genomic diversity, resistance patterns, impact of polymorphisms in disease susceptibility, and taxa-induced dysbiosis in microbiomes. Additionally, this work highlighted the outcome of bioinformatic studies in predicting suitable vaccine epitopes, and novel drug targets to combat MAC infections. Bioinformatic research on bacteria within MAC has contributed to a deeper insight into the pathogens. These would facilitate better diagnosis, improved: therapeutic strategies, patient-specific surveillance, and community-level awareness. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies have investigated the role of different factors in paratuberculosis introduction in dairy farms or dairy cattle. Because paratuberculosis between-herd prevalence was shown to differ substantially between three regions of Germany, this study evaluated different management factors for their impact on the paratuberculosis status of a farm. The most obvious impact was found for an increase of 100 or more cows per herd, followed by the purchase of cattle with unknown paratuberculosis status and limitations in calf feeding management within the barn. These aspects should be prioritized in paratuberculosis control beneath a tailored control approach for individual farms and regions. In a cross-sectional study, it was identified that three regions in Germany differed with respect to their herd-level prevalence for paratuberculosis in dairy cattle. In the study presented here, the same farms were analyzed to identify those components of biosecurity and farm management with the highest impact on Mycobacterium avium ssp. paratuberculosis (MAP) introduction and establishment in a farm. Hence, the data analyzes included 183, 170 and 104 herds from the study regions north, east and south, respectively. A herd was considered MAP-positive if at least one fecal environmental sample was positive. Twenty-six different possible risk factors from five different components of biosecurity and farm management were analyzed. We show that the average management of calf feeding increased the odds for a MAP-positive farm by 5.22 times (95% confidence interval (CI) = 1.25–21.83). With every 100-cow increase in farm size, the risk for a farm to test MAP-positive increased by 1.94 times (CI = 1.15–3.27), 1.14 times (CI = 1.02–1.27) and 5.53 times (CI = 0.44–68.97) in the north, east and south study regions, respectively. Furthermore, the purchase of cattle with an unknown MAP status increased the risk for a farm testing MAP-positive by 2.86-fold (CI = 1.45–5.67). Our results demonstrate that herd size, unknown MAP status of the purchased cattle and different aspects of calf feeding play an important role in the MAP status of a farm and should be in focus in regions with different MAP between-herd prevalence. Additionally, farm individual risk patterns should be identified during (veterinary) biosecurity consultancy. [ABSTRACT FROM AUTHOR]

Objectives: Limited data are available on the progression of pulmonary Mycobacterium avium complex (MAC) disease without culture-positive sputum. The aim of this study was to identify the risk factors associated with clinical progression of pulmonary MAC disease diagnosed by bronchoscopy. Methods: A single-center, retrospective, observational study was conducted. Pulmonary MAC patients diagnosed by bronchoscopy without culture-positive sputum from January 1, 2013, to December 31, 2017 were analyzed. Clinical progression after diagnosis was defined as having culture-positive sputum at least once or initiation of guideline-based therapy. Then, clinical characteristics were compared between clinically progressed patients and stable patients. Results: Ninety-three pulmonary MAC patients diagnosed by bronchoscopy were included in the analysis. During the 4-year period after diagnosis, 38 patients (40.9%) started treatment, and 35 patients (37.6%) had new culture-positive sputum. Consequently, 52 patients (55.9%) were classified into the progressed group, and 41 patients (44.1%) were classified into the stable group. There were no significant differences between the progressed and the stable groups in age, body mass index, smoking status, comorbidities, symptoms, or species isolated from bronchoscopy. On multivariate analysis, male sex, monocyte to lymphocyte ratio (MLR) ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were risk factors for clinical progression. Conclusions: Some patients with pulmonary MAC disease without culture-positive sputum progress within 4 years. Therefore, pulmonary MAC patients, especially male patients, having higher MLR or lesions in the middle (lingula) and lower lobes might need careful follow-up for a longer time. [ABSTRACT FROM AUTHOR]

Background and Aim: Paratuberculosis (PTB) or John's disease is a chronic disease of ruminants impeding the reproduction and productivity of the livestock sector worldwide. Since there is a lack of pathological studies explaining the nature and development of the disease in camels, this study aimed to highlight the anatomopathological changes of PTB in camels, which may help in verifying and validating some diagnostic tests used to detect the etiology of the disease in camel tissues. Materials and Methods: In August 2017, at Alselaa border's Veterinary Clinic of Al Dhafra Region, Western Abu Dhabi, UAE, one imported culled she-camel of 2 years old was subjected to clinical, microscopic, and anatomopathological investigations along with real-time quantitative polymerase chain reaction (q-PCR) to confirm the infection and correlate between clinical signs and pathological lesions of the PTB in dromedary camels. Results: Clinically, typical clinical signs compliant with the pathognomonic gross and histologic lesions of PTB were seen in naturally infected dromedary camel. As presumptive diagnosis microscopically, acid-fast coccobacillus bacterium clumps were demonstrated in direct fecal smears as well as in scraped mucosal and crushed mesenteric lymph node films, and in histopathological sections prepared from a necropsied animal and stained by Ziehl-Neelsen stain. Free and intracellular acid-fast clump phagosomes were further confirmed as Mycobacterium avium subsp. paratuberculosis by q-PCR. Conclusion: Clinical signs and pathological lesions of paratuberculosis in a dromedary camel were found to be similar to those of the other susceptible hosts. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of Johne's disease (JD) due to Mycobacterium avium ssp. paratuberculosis (Map), responsible for considerable economic losses in the dairy industry worldwide, remains very high. In addition, recent studies have shown that Map may hamper the success of bovine tuberculosis (bTB) eradication programs due to frequent co-infection of hosts. Therefore, the risk of Map contamination by environmental sources must be studied given achieving improved control of this enzooty. Our previous work showed that environmental amoebae could function as reservoirs and vectors of these pathogenic mycobacteria. This study aims to describe amoeba-mycobacteria co-occurrence by sampling the water points of cattle herds monitored for Map and Mycobacterium bovis (M. bovis) infection. Our study showed that a wide diversity of amoebae and non-tuberculous mycobacteria (NTM) species, including Map, live closely together in water troughs of herds monitored for JD or bTB. The exact association between amoebae and mycobacteria calls for further investigation. One of the obstacles to eradicating paratuberculosis or Johne's Disease (JD) seems to be the persistence of Mycobacterium avium subsp. paratuberculosis (Map) in the environment due to its ability to survive alone or vectorized. It has been shown that Map is widely distributed in soils and water. Previously, we isolated amoebae associated with Map strains in the environment of bovines from an infected herd. This work aims to verify our working hypothesis, which suggests that amoebae may play a role in the transmission of JD. In this study, we sampled water in the vicinity of herds infected with Map or Mycobacterium bovis (M. bovis) and searched for amoebae and mycobacteria. Live amoebae were recovered from all samples. Among these amoebae, four isolates associated with the presence of mycobacteria were identified and characterized. Map and other mycobacterial species were detected by qPCR and, in some cases, by culture. This study suggests that amoebae and Map may be found in the same environment and might represent a risk of exposure of animals to pathogenic mycobacteria. These data open up new perspectives on the control measures to be put in place to prevent contamination by Map. [ABSTRACT FROM AUTHOR]

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne's disease, a severe gastroenteritis of ruminants. This study developed a model cell culture system to rapidly screen MAP mutants with vaccine potential for apoptosis. Two wild-type strains, a transposon mutant, and two deletion mutant MAP strains (MOI of 10 with 1.2 × 106 CFU) were tested in murine RAW 264.7 macrophages to determine if they induce apoptosis and/or necrosis. Both deletion mutants were previously shown to be attenuated and immunogenic in primary bovine macrophages. All strains had similar growth rates, but cell morphology indicated that both deletion mutants were elongated with cell wall bulging. Cell death kinetics were followed by a real-time cellular assay to measure luminescence (apoptosis) and fluorescence (necrosis). A 6 h infection period was the appropriate time to assess apoptosis that was followed by secondary necrosis. Apoptosis was also quantified via DAPI-stained nuclear morphology and validated via flow cytometry. The combined analysis confirmed the hypothesis that candidate vaccine deletion mutants are pro-apoptotic in RAW 264.7 cells. In conclusion, the increased apoptosis seen in the deletion mutants correlates with the attenuated phenotype and immunogenicity observed in bovine macrophages, a property associated with good vaccine candidates. [ABSTRACT FROM AUTHOR]

Pathobionts, particularly Mycobacterium avium subsp. paratuberculosis (MAP) and Escherichia coli isolates with adherence/invasive ability (AIEC) have been associated with inflammatory bowel disease (IBD), particularly Crohn's disease (CD). This study aimed to evaluate the frequency of viable MAP and AIEC in a cohort of IBD patients. As such, MAP and E. coli cultures were established from faecal and blood samples (with a total n = 62 for each) of patients with CD (n = 18), ulcerative colitis (UC, n = 15), or liver cirrhosis (n = 7), as well as from healthy controls (HC, n = 22). Presumptive positive cultures were tested by polymerase chain reaction (PCR), for a positive confirmation of MAP or E. coli identity. E. coli-confirmed isolates were then tested for AIEC identity using adherence and invasion assays in the epithelial cell line of Caco-2 and survival and replication assays in the macrophage cell line of J774. MAP sub-culture and genome sequencing were also performed. MAP was more frequently cultured from the blood and faecal samples of patients with CD and cirrhosis. E. coli presumptive colonies were isolated from the faecal samples of most individuals, in contrast to what was registered for the blood samples. Additionally, from the confirmed E. coli isolates, only three had an AIEC-like phenotype (i.e., one CD patient and two UC patients). This study confirmed the association between MAP and CD; however, it did not find a strong association between the presence of AIEC and CD. It may be hypothesized that the presence of viable MAP in the bloodstream of CD patients contributes to disease reactivation. [ABSTRACT FROM AUTHOR]

Mycobacterium avium subspecies paratuberculosis (MAP) causes paratuberculosis (PTB), which is a granulomatous enteritis in ruminants that threatens the dairy industry's healthy development and public health safety worldwide. Because the commercial inactivated vaccines are not completely protective and interfere with bovine tuberculosis diagnostics, we tested four fusion proteins, namely 66NC, 66CN, 90NC, and 90CN, which were constructed with MAP3527, Ag85B, and Hsp70 of MAP in different tandem combinations. Notably, 66NC, which encodes a 66 kDa fusion protein that combines in linear order MAP3527N40–232, Ag85B41–330, and MAP3527C231–361, induced a powerful and specific IFN-γ response. Immunization of C57BL/6 mice with the 66NC fusion protein formulated in Montanide ISA 61 VG adjuvant generated robust Th1, Th2, and Th17 type immune responses and strong antibody responses. The 66NC vaccine protected C57BL/6 mice against virulent MAP K-10 infection. This resulted in a reduction of bacterial load and improvement of pathological damage in the liver and intestine, in addition to a reduction of body weight loss; significantly better protection than the reported 74 F vaccine was also induced. Furthermore, vaccine efficacy correlated with the levels of IFN-γ-, TNF-α-, and IL-17A-secreting antigen-specific CD4+ and CD8+ T lymphocytes as well as with serum IFN-γ and TNF-α levels after vaccination. These results demonstrate that recombinant protein 66NC is an efficient candidate for further development into a protective vaccine in terms of inducing specific protection against MAP. [ABSTRACT FROM AUTHOR]

Simple Summary: Paratuberculosis (PTB) is a well-known disease with considerable financial impact on the farm industry worldwide. Nevertheless, data regarding the assessment of naturally infected goat herds is limited. The present study describes in detail the observed gross and histological lesions detected in 39 necropsies of goats (15 vaccinated and 24 non-vaccinated) from herds with a confirmed history of PTB. PTB microscopic lesions of various grades were detected in all animals in target organs and the presence of the causative agent was confirmed using different laboratory tools. The main inflammatory findings affected the hemolymphatic, respiratory and gastrointestinal systems. The lesions were confirmed microscopically with lesser macroscopically visible alterations. Our result demonstrated that non-vaccinated animals presented more severe PTB intestinal lesions and had respiratory inflammation in all age groups studied. Those also presented a higher prevalence of ileocecal valve PTB lesions. Gastrointestinal non-PTB lesions were detected in higher number in non-vaccinated goats. Thus, histology is a powerful tool for herd diagnosis and assessment. Mainly inflammatory lesions of the respiratory and gastrointestinal tract were detected in the studied PTB-affected herds. Additionally, vaccination against PTB could play a key role in the reduction of lung and gastrointestinal inflammatory processes present in the herd. Paratuberculosis (PTB), caused by Mycobacterium avium subspecies paratuberculosis (MAP), causes significant financial losses in the ruminant industry. The aim of this study is to describe the concomitant pathological findings as well as PTB-induced lesions in 39 naturally infected goats (15 vaccinated and 24 non-vaccinated). All animals exhibited MAP-induced microscopic lesions affecting target organs, although only 62% of those were detected grossly. Mainly concomitant inflammatory pathologies were recognized affecting the hemolymphatic, respiratory and gastrointestinal systems. Non-vaccinated animals exhibited both moderate and marked granulomatous enteritis in contrast with vaccinated ones which presented mild intestinal affection. Our results demonstrate that non-vaccinated animals presented pneumonia in all age groups studied (from 12 up to >48 months old). A significantly higher prevalence of ileocecal valve PTB lesions was detected in non-vaccinated animals with pneumonic lesions (p = 0.027). Furthermore, a reduction of gastrointestinal non-PTB processes was described in vaccinated goats. In conclusion, a PTB infected goat herd can be affected by a wide range of concomitant pathologies, mostly inflammatory in origin. Anatomic pathology is of crucial importance for correct herd diagnosis and histopathology is an indispensable tool for lesion detection. Additionally, anti-MAP vaccination could have a beneficial effect on the reduction of respiratory and gastrointestinal non-PTB diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Paratuberculosis is a chronic inflammatory disease leading to emaciation and production losses in ruminants. Important aspects of disease control are the detection of infected herds and environmental areas where contact between animals and the causative pathogen Mycobacterium avium subsp. paratuberculosis (MAP) is possible. Bedding, dust, feed, and water samples were collected from the barn of a paratuberculosis-infected dairy goat herd and analyzed for culturable MAP and MAP DNA. Cultivation was successful in 28 bedding and one dust sample, while MAP DNA was detected in 117 out of 256 samples from all materials. Samples collected from areas of high animal traffic, such as the milking parlor, were more likely to reveal positive results than adult and young goat areas. Positive culture results were also obtained from kidding pens, constituting this barn area as a possible infection site. Overall, environmental sampling may be suitable for the detection of MAP in goat herds and the identification of potential critical areas for pathogen transmission. These results should be taken into account for paratuberculosis control programs in goat herds to improve their efficiency and, thus, animal welfare. Environmental samples are often used to classify the paratuberculosis status of cattle herds. The disease is caused by Mycobacterium avium subsp. paratuberculosis (MAP), predominantly through oral ingestion during infancy. In this explorative study, the presence of MAP was determined in the barn environment of a paratuberculosis-infected vaccinated dairy goat herd. A total of 256 bedding, dust, feed, and water samples were collected at eight time points and examined using culture and qPCR. Detection rates of both methods were compared, and factors determining MAP confirmation were identified. MAP was cultured from 28 bedding and one dust sample, while MAP DNA was detected in all materials (117/256). Samples from high animal traffic areas and those collected during the indoor season were more likely to yield positive culture and qPCR results. Cultivation of MAP from kidding pens indicated this area as a possible infection site. Dust proved to be the most suitable material for detecting MAP DNA, as bedding was for MAP culture. Environmental sampling was demonstrated to be an effective way to detect MAP in a dairy goat herd. qPCR results could confirm herd infection, while culture results provided insight into crucial areas for MAP transmission. These findings should be considered when designing farm-specific paratuberculosis control plans. [ABSTRACT FROM AUTHOR]

Simple Summary: Johne's disease is a global economic burden. The disease contributes to reduced milk yield, reduced fertility, higher rates of susceptibility to other diseases and eventual death. Unhealthy animals are less efficient, producing higher kg of greenhouse gases per kg of output (milk and meat). Therefore, prognosis and diagnosis are important in terms of animal welfare and future climate change policies by reducing the impact of livestock on climate change. In the past decade, our knowledge around the microbiome in health and disease has increased. Next generation sequencing technologies have provided a new understanding of the interactions between the host microbiome and pathogens. The microbiome is a target for treatment, prevention of disease and a source of novel biomarkers of disease risk. The potential to improve animal health is highly dependent on our ever growing knowledge of the gut microbiome and their interactions with the host. With the aim to gain knowledge in the early months of exposure to MAP in calves, we investigated the dynamics of the gut microbiome (using faecal sample) of calves 3, 6 and 9 months post inoculation with MAP relative to unexposed controls. Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease in ruminants, a chronic enteritis which results in emaciation and eventual loss of the animal. Recent advances in metagenomics have allowed a more in-depth study of complex microbiomes, including that of gastrointestinal tracts, and have the potential to provide insights into consequences of the exposure of an animal to MAP or other pathogens. This study aimed to investigate taxonomic diversity and compositional changes of the faecal microbiome of cattle experimentally challenged with MAP compared to an unexposed control group. Faecal swab samples were collected from a total of 55 animals [exposed group (n = 35) and a control group (n = 20)], across three time points (months 3, 6 and 9 post-inoculation). The composition and functional potential of the faecal microbiota differed across time and between the groups (p < 0.05), with the primary differences, from both a taxonomic and functional perspective, occurring at 3 months post inoculation. These included significant differences in the relative abundance of the genera Methanobrevibacter and Bifidobacterium and also of 11 other species (4 at a higher relative abundance in the exposed group and 7 at a higher relative abundance in the control group). Correlations were made between microbiome data and immunopathology measurements and it was noted that changes in the microbial composition correlated with miRNA-155, miR-146b and IFN-ɣ. In summary, this study illustrates the impact of exposure to MAP on the ruminant faecal microbiome with a number of species that may have relevance in veterinary medicine for tracking exposure to MAP. [ABSTRACT FROM AUTHOR]

Simple Summary: Paratuberculosis is an economically important disease in ruminants, and control in affected herds/flocks primarily relies on test and cull strategies and good hygiene and management practices. Vaccination against the causative agent Mycobacterium avium subsp. paratuberculosis is also used as a tool in some paratuberculosis control programs. The effects of the whole-cell heat-killed Silirum® vaccine on bacterial shedding in the feces and serological response were studied in a controlled field study involving seven French dairy herds, where calves were vaccinated at various ages. A statistically significant reduction of the probability of fecal shedding was observed for cows vaccinated before 4 to 5 months of age compared to non-vaccinated controls. A strong effect of age at vaccination on the serological status investigated in adulthood was also demonstrated, which was also associated with a difference in the protective effect of vaccination. (1) Background: paratuberculosis is an important disease in ruminants, causing worldwide economic losses to the livestock industry. Although vaccination is known not to prevent transmission of the causative agent Mycobacterium avium subsp. paratuberculosis (Map), it is considered an effective tool for paratuberculosis in infected herds. The objectives of this controlled field study were to evaluate the effects of the whole-cell heat-killed Silirum® vaccine on Map fecal shedding and serological status in dairy herds infected with paratuberculosis. (2) Methods: The serological status (ELISA) and fecal shedding (qPCR) of 358 vaccinated cows were assessed over 3 years in 7 infected dairy herds in the Meuse department, France. Within each herd, cows from the last non-vaccinated birth cohort (n = 265) were used as controls. The probability and level of Map fecal shedding and the serological status were modeled using multivariable mixed general linear regression models. (3) Results: Overall, 34.7% of cows tested positive at least once on fecal qPCR, with significant differences between herds, but high shedding levels were observed in only 5.5% of cows. Compared to non-vaccinated seronegative cows, a statistically significant reduction in the probability of Map shedding was found only in cows vaccinated before 4 to 5 months of age that tested negative for Map antibodies throughout the study period (odds ratio = 0.5, 95% confidence interval: 0.3–0.9, p = 0.008), but no significant effect of vaccination on the amount of Map shedding could be evidenced. Finally, the younger the cows were when vaccinated, the less they tested positive on the serum ELISA. (4) Conclusions: a beneficial effect of vaccination on Map fecal shedding may exist in cows vaccinated before 4 to 5 months of age. The variability of the serum ELISA response in vaccinated cows remains to be investigated. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to investigate the occurrence of paratuberculosis (Johne's disease), caused by Mycobacterium avium subsp. paratuberculosis (MAP), in Austrian sheep and goats by testing 22,019 blood samples. Furthermore, detailed investigations in five MAP-infected goat herds were carried out to detect the disease in blood and faecal samples. The detected animal MAP seroprevalence was 2.0% for goats and 0.7% for sheep (calculated true prevalence 3.5% and 1.2%, respectively). Herd-level apparent MAP seroprevalence was 11.1% for goat herds and 8.9% for sheep flocks. Herds with a more intensive production system had a significantly higher risk of being infected, as well as farms with frequent trading of animals or where other ruminant species were kept on the same premise. In the five goat farms investigated, 21.8% (11.7%–28.0%, calculated true seroprevalence 38.6%) of the animals were found to be infected and 12.3% (5.0%–24.7%) of the animals were shedding the bacterium with their faeces. It was further possible to identify the bacterium using boot swab samples from the stable environment in each of the five herds. The results indicated a moderate paratuberculosis infection rate in small ruminants in Austria. This study aimed to investigate the prevalence of Mycobacterium avium subsp. paratuberculosis (MAP) in small ruminants in Austria by testing 22,019 serum samples with ELISA for the presence of specific antibodies. Furthermore, detailed investigations in five MAP-infected goat herds were carried out by ELISA, qPCR and bacterial culture. The found animal-level apparent MAP seroprevalence was 2.0% for goats and 0.7% for sheep (calculated true prevalence 3.5% and 1.2%, respectively). Herd-level apparent MAP seroprevalence was 11.1% for goat herds and 8.9% for sheep flocks. Significant risk factors for seropositivity in goat herds were: herd size, animal trading, farmed as a dairy herd, Animal Health Service membership and cohabitation with farmed game. For sheep flocks, seroprevalence was significantly higher in flocks with animal trading and where cattle or goats were kept in the flock, respectively. The overall apparent within-herd MAP seroprevalence in the five goat farms investigated was 21.8% (11.7%–28.0%, calculated true seroprevalence 38.6%) and an overall rate of MAP shedding of 12.3% was detected (5.0%–24.7%). It was possible to identify MAP by culture using boot swab samples in each herd. The results indicated a moderate MAP infection rate in small ruminants in Austria. [ABSTRACT FROM AUTHOR]

Paratuberculosis, also known as Johne's (Yo'-ness) disease, is a significant bacterial disease of large and small ruminants, including other animals, caused by Mycobacterium avium subspecies paratuberculosis (MAP). Due to its impact on animal health and severe economic loss, the disease is recognized and reported in developed countries as a significant disease of livestock importance. The paper aims to review the current information about paratuberculosis in Nigeria. About 95 research articles were downloaded from various online journals databases such as Scopus, Google Scholar, Research Gate, PubMed, and CABI abstracts based on the following keywords: Johne's disease, paratuberculosis, Africa, prevalence, Nigeria, report, occurrence, and Mycobacterium avium subspecies paratuberculosis. In addition to the perusal of organization databases, 60 research articles were used in writing this review article. Few cases and suspected cases of paraTB were reported in Nigeria by the World Organization for Animal Health (OIE). Despite growing global concerns, Johne's disease can be considered an unreported disease of livestock animals in Nigeria based on the knowledge gap and lack of reports about this significant disease of livestock animals. Studies need to be carried out to address the knowledge gaps before the disease becomes endemic and causes severe economic and public health menace in Nigeria and, by extension, Sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Antibiotic resistance (AR) and multidrug resistance (MDR) have been confirmed for all major foodborne pathogens: Campylobacter spp., Salmonella spp., Escherichia coli and Listeria monocytogenes. Of great concern to scientists and physicians are also reports of antibiotic-resistant emerging food pathogens—microorganisms that have not previously been linked to food contamination or were considered epidemiologically insignificant. Since the properties of foodborne pathogens are not always sufficiently recognized, the consequences of the infections are often not easily predictable, and the control of their activity is difficult. The bacteria most commonly identified as emerging foodborne pathogens include Aliarcobacter spp., Aeromonas spp., Cronobacter spp., Vibrio spp., Clostridioides difficile, Escherichia coli, Mycobacterium paratuberculosis, Salmonella enterica, Streptocccus suis, Campylobacter jejuni, Helicobacter pylori, Listeria monocytogenes and Yersinia enterocolitica. The results of our analysis confirm antibiotic resistance and multidrug resistance among the mentioned species. Among the antibiotics whose effectiveness is steadily declining due to expanding resistance among bacteria isolated from food are β-lactams, sulfonamides, tetracyclines and fluoroquinolones. Continuous and thorough monitoring of strains isolated from food is necessary to characterize the existing mechanisms of resistance. In our opinion, this review shows the scale of the problem of microbes related to health, which should not be underestimated. [ABSTRACT FROM AUTHOR]

Mycobacterium avium subspecies paratuberculosis (MAP) is a chronic, contagious, and typically life-threatening enteric disease of ruminants caused by a bacterium of the genus Mycobacterium, but it can also affect non-ruminant animals. MAP transmission occurs through the fecal–oral pathway in neonates and young animals. After infection, animals generate IL-4, IL-5, and IL-10, resulting in a Th2 response. Early detection of the disease is necessary to avoid its spread. Many detection methods, viz., staining, culture, and molecular methods, are available, and numerous vaccines and anti-tuberculosis drugs are used to control the disease. However, the prolonged use of anti-tuberculosis drugs leads to the development of resistance. Whereas vaccines hamper the differentiation between infected and vaccinated animals in an endemic herd. This leads to the identification of plant-based bioactive compounds to treat the disease. Bioactive compounds of Ocimum sanctum and Solanum xanthocarpum have been evaluated for their anti-MAP activity. Based on the MIC50 values, Ursolic acid (12 µg/mL) and Solasodine (60 µg/mL) were found to be suitable for anti-MAP activity. [ABSTRACT FROM AUTHOR]

Background and Aim: Brucellosis, paratuberculosis (PTb), and infections caused by small ruminant lentivirus (SRLV), formerly known as caprine arthritis encephalitis virus (CAEV), adversely affect goat production systems. Nonetheless, commonly used diagnostic tests can only determine one analyte at a time, increasing disease surveillance costs, and limiting their routine use. This study aimed to design and validate a multiplex assay for antibody detection against these three diseases simultaneously. Materials and Methods: Two recombinant proteins from the SRLV (p16 and gp38), the native hapten of Brucella melitensis, and the paratuberculosis-protoplasmic antigen 3 from Mycobacterium avium subsp. paratuberculosis (MAP) were used to devise and assess a multiplex assay. Conditions for the Luminex® multiplex test were established and validated by sensitivity, specificity, repeatability, and reproducibility parameters. Cut-off points for each antigen were also established. Results: The 3-plex assay had high sensitivity (84%) and specificity (95%). The maximum coefficients of variation were 23.8% and 20.5% for negative and positive control samples, respectively. The p16 and gp38 SRLV antigens are 97% and 95%, similar to the CAEV sequence found in GenBank, respectively. Conclusion: The multiplex test can be effectively used for the simultaneous detection of antibodies against SRLV, MAP and B. melitensis in goats. [ABSTRACT FROM AUTHOR]

Johne's disease is an infectious disease affecting cattle, other ruminants and non-ruminant wildlife worldwide, caused by Mycobacterium avium subspecies paratuberculosis (MAP). This review provides an up-to-date concise overview of the pathogenesis of MAP, the significance of Johne's disease in cattle and the use of diagnostic testing at both animal and herd level in the context of seasonal pasture-based herds. While MAP can only replicate intracellularly, the bacterium is sufficiently robust to survive for months in the environment. Transmission of MAP is mostly via the faecal-oral route, however in-utero transmission in also possible. The bacteria evade the immune system by persisting in macrophages in the small intestine submucosa, with this latent stage of infection lasting, in most cases, for at least two years before bacterial shedding and clinical signs begin. The slowly progressive nature of MAP infection, poor performance of diagnostic tests and management systems that expose susceptible calves to infection make control of Johne's disease challenging, particularly in seasonal calving herds. Testing of individual animals provides little assurance for farmers and vets due to the poor sensitivity and, in the case of ELISA, imperfect specificity of the available tests. Repeated herd-level testing is utilised by the IJCP to detect infected herds, identify high risk animals, and provide increasing confidence that test-negative herds are free of infection. The IJCP aims to control the spread of Johne's disease in cattle in Ireland, in order to protect non-infected herds, limit the economic and animal health impact of the disease, improve calf health and reassure markets of Johne's disease control in Ireland. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy is an essential adaptive physiological response in eukaryotes induced during nutrient starvation, including glucose, the primary immediate carbon and energy source for most cells. Although the molecular mechanisms that induce autophagy during glucose starvation have been extensively explored in the budding yeast Saccharomyces cerevisiae, little is known about how this coping response is regulated in the evolutionary distant fission yeast Schizosaccharomyces pombe. Here, we show that S. pombe autophagy in response to glucose limitation relies on mitochondrial respiration and the electron transport chain (ETC), but, in contrast to S. cerevisiae, the AMP-activated protein kinase (AMPK) and DNA damage response pathway components do not modulate fission yeast autophagic flux under these conditions. In the presence of glucose, the cAMP-protein kinase A (PKA) signaling pathway constitutively represses S. pombe autophagy by downregulating the transcription factor Rst2, which promotes the expression of respiratory genes required for autophagy induction under limited glucose availability. Furthermore, the stress-activated protein kinase (SAPK) signaling pathway, and its central mitogen-activated protein kinase (MAPK) Sty1, positively modulate autophagy upon glucose limitation at the transcriptional level through its downstream effector Atf1 and by direct in vivo phosphorylation of Rst2 at S292. Thus, our data indicate that the signaling pathways that govern autophagy during glucose shortage or starvation have evolved differently in S. pombe and uncover the existence of sophisticated and multifaceted mechanisms that control this self-preservation and survival response. [ABSTRACT FROM AUTHOR]

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Background: Bacteria are capable of responding to various stressors, something which has been essential for their adaptation, evolution, and colonization of a wide range of environments. Of the many stressors affecting bacteria, we can highlight heavy metals, and amongst these, copper stands out for its great antibacterial capacity. Using Mycobacterium tuberculosis (Mtb) as a model, the action of proteins involved in copper homeostasis has been put forward as an explanation for the tolerance or adaptive response of this mycobacteria to the toxic action of copper. Therefore, the aim of this study was to confirm the presence and evaluate the expression of genes involved in copper homeostasis at the transcriptional level after challenging Mycobacterium avium subsp. paratuberculoisis (MAP) with copper ions. Methodology: Buffer inoculated with MAP was treated with two stressors, the presence of copper homeostasis genes was confirmed by bioinformatics and genomic analysis, and the response of these genes to the stressors was evaluated by gene expression analysis, using qPCR and the comparative ΔΔCt method. Results: Through bioinformatics and genomic analysis, we found that copper homeostasis genes were present in the MAP genome and were overexpressed when treated with copper ions, which was not the case with H2O2 treatment. Conclusion: These results suggest that genes in MAP that code for proteins involved in copper homeostasis trigger an adaptive response to copper ions. [ABSTRACT FROM AUTHOR]

Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago, "anonymous mycobacteria" were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement, though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma—while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium subsp. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn's disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the "non-cheesy" granuloma of sarcoidosis actually contains the difficult-to-detect "cheese", MAP; MAP did not move, it was there all along. [ABSTRACT FROM AUTHOR]

Enterohemorrhagic Escherichia coli O157 (O157) strains can be subdivided into clades based on their single-nucleotide polymorphisms, but such analysis using conventional methods requires intense effort by laboratories. Although multi-locus variable-number tandem repeat analysis (MLVA), which can be performed with low laboratory burden, has been used as a molecular epidemiological tool, it has not been evaluated whether MLVA can be used the clade subdivision of O157 strains like it can for that of other pathogenic bacteria. This study aimed to establish a method for subdividing O157 strains into clades using MLVA data. The standardized index of association, ISA, for O157 strains isolated in Chiba prefecture, Japan (Chiba isolates) revealed the presence of unique tandem repeat patterns in each major clade (clades 2, 3, 7, 8, and 12). A likelihood database of tandem repeats for these clades was then constructed using the Chiba isolates, and a formula for maximum a posteriori (MAP) estimation was constructed. The ratio of the number of O157 strains putatively subdivided into a clade by MAP estimation from MLVA data relative to the number of O157 strains subdivided using single-nucleotide polymorphism analysis (designated as the concordance ratio [CR]) was calculated using the Chiba isolates and O157 strains isolated in Yamagata prefecture (Yamagata isolates). The CRs for the major Chiba and Yamagata isolate clades, other than clade 2, were 89%–100%. Although the CR for clade 2 Chiba isolates was >95%, that of the Yamagata isolates was only 78.9%. However, these clade 2 CRs were not significantly different from one another, indicating that clade 2 strains can be subdivided correctly by MAP estimation. In conclusion, this study expands the utility of MLVA, previously applied predominantly for molecular epidemiological analysis, into a low-laboratory-burden tool for subdividing O157 strains into phylogenetic groups. [ABSTRACT FROM AUTHOR]

There has been little success in controlling Johne’s disease, caused by Mycobacterium avium subsp. paratuberculosis, due to suboptimal diagnostics and the ineffectiveness of available vaccines. By knocking out BacA and IcL, genes required for MAP survival in dairy calves, two live-attenuated vaccine candidates were created. This study evaluated the host-specific attenuation of MAP IcL and BacA mutants in mouse and calf models, as well as the elicited immune responses. Deletion mutants were generated in MAP strain A1-157 through specialized transduction and found viable in vitro. First, the mutants’ attenuation and elicited cytokine secretion were assessed in a mouse model, 3 weeks after intraperitoneal inoculation with MAP strains. Later, vaccine strains were assessed in a natural host infection model where calves received 109CFU oral dose of MAP wild-type or mutant strains at 2 weeks old. Transcription levels of cytokines in PBMCs were evaluated at 12-, 14-, and 16-weeks post-inoculation (WPI) and MAP colonization in tissue was assessed at 4.5 months after inoculation. Whereas both vaccine candidates colonized mouse tissues similarly to wild-type strain, both failed to persist in calf tissues. In either mouse or calf models, gene deletion did not reduce immunogenicity. Instead, inoculation with ΔBacA induced a greater upregulation of proinflammatory cytokines than ΔIcL and wild-type in both models and a greater expansion of cytotoxic and memory T-cells than uninfected control in calves. ΔBacA and wild-type strains significantly increased secretion of IP-10, MIG, TNFα, and RANTES in mice serum compared to uninfected control. This agreed with upregulation of IL-12, IL-17, and TNFα in calves inoculated with ΔBacA at all time points. The ΔBacA also gave rise to greater populations of CD4+CD45RO+, and CD8+ cells than uninfected control calves at 16 WPI. Low survival rate of MAP in macrophages co-incubated with PBMCs isolated from the ΔBacA group indicated that these cell populations are capable of killing MAP. Overall, the immune response elicited by ΔBacA is stronger compared to ΔIcL and it is maintained over two different models and over time in calves. Further investigation is warranted to evaluate the BacA mutant's protection against MAP infection as a live attenuated vaccine candidate. [ABSTRACT FROM AUTHOR]

Simple Summary: Paratuberculosis is a bacterial infection occurring globally in ruminants. Although it has a known impact on animal health and welfare, diagnosis is complicated by high animal densities, the chronic nature of the disease, the variable course of infection, and the immune response. The aim of the current study was to confirm whether Mycobacterium avium sp. paratuberculosis (MAP) infections occur in zoo animals in Poland. Faeces samples (n = 131) were collected for analysis from different species of animals from eight zoos in Poland. Our study provides the first confirmation of MAP in bongo antelope and confirms that MAP is present in Polish zoological gardens and requires monitoring, which can be easier now due to new legislation. Mycobacterial infections are significant issues in zoo animals, influencing animal welfare, conservation efforts, and the zoonotic potential of pathogens. Although tuberculosis is recognised to be highly dangerous, paratuberculosis can also lead to animal losses and is potentially dangerous for humans. The aim of the current study was to confirm whether Mycobacterium avium spp. paratuberculosis (MAP) infections are currently present in zoos in Poland. Faeces samples (n = 131) were collected from different animal species from eight zoos in Poland. The faeces were decontaminated and inoculated into Herrold's Egg Yolk Media. The species was determined using commercial DNA testing. The IS900 was checked using RT-PCR. The culture was positive in seven samples: five with M. avium, one with Mycobacterium fortiatum, and one without any identified Mycobacterium species. RT-PCR confirmed MAP genetic material in nine animals. Our findings represent the first confirmation of MAP in bongo (Tragelaphus eurycerus), indicating that it is present in Polish zoological gardens. Fortunately, the disease can be monitored more easily due to recent legislation (the Animal Health Law). [ABSTRACT FROM AUTHOR]

Increasing attention is being paid to the unique roles gut microbes play in both physiological and pathological processes. Crohn's disease (CD) is a chronic, relapsing, inflammatory disease of the gastrointestinal tract with unknown etiology. Currently, gastrointestinal infection has been proposed as one initiating factor of CD. Yersinia enterocolitica, a zoonotic pathogen that exists widely in nature, is one of the most common bacteria causing acute infectious gastroenteritis, which displays clinical manifestations similar to CD. However, the specific role of Y. enterocolitica in CD is controversial. In this Review, we discuss the current knowledge on how Y. enterocolitica and derived microbial compounds may link to the pathogenesis of CD. We highlight examples of Y. enterocolitica-targeted interventions in the diagnosis and treatment of CD, and provide perspectives for future basic and translational investigations on this topic. [ABSTRACT FROM AUTHOR]

Testing of bulk milk (BM) samples is a convenient, cost-effective strategy that can easily be implemented as part of disease surveillance programs on dairy farms. Here, we performed a scoping review to summarize the literature reporting on the testing of BM samples to detect infectious diseases of dairy cattle caused by bacteria. We also provide a non-exhaustive, albeit significant, list of diagnostic tests that are marketed for BM samples, as well as a list of disease surveillance activities that included testing of BM samples. A literature search was carried out in 5 databases, yielding 8,829 records from which 474 were retained. Overall, 575 eligible bacterial pathogens were screened for using BM samples, ranging from 1 to 6 individual pathogens per study. Staphylococcus aureus , including methicillin-resistant Staph. aureus , were the most studied bacteria (n = 179 studies), followed by Streptococcus agalactiae (86), Mycobacterium avium ssp. paratuberculosis (79), Coxiella burnetii (79), and Mycoplasma spp. (67). Overall, culture-based protocols, ELISA, real-time PCR, and PCR were the most commonly adopted methodologies to screen BM samples. Sensitivity of BM testing for bovine paratuberculosis was generally low and varied greatly according to the ELISA cut-offs adopted and herd-level definition of disease. In general, protocols had low to moderate sensitivities (<50%), which increased for herds with high within-herd seroprevalence. Specificity of BM testing for paratuberculosis was generally high. With respect to mastitis pathogens, BM testing demonstrated high sensitivity and specificity for Strep. agalactiae , in general. However, we observed inconsistency among studies with respect to the sensitivity of BM culture to detect infected herds, which was notably higher if enrolled herds were heavily infected or had history of clinical disease. Among Salmonella spp. pathogens, Salmonella Dublin was the most frequently studied bacterium for which BM testing has been validated. Specificity of BM ELISA was high, ranging from 89.0 to 99.4. In contrast, sensitivity varied greatly among studies, ranging from 50.6% to 100%. Our findings support that one of most important factors affecting sensitivity of BM ELISA for Salmonella Dublin is whether nonlactating cattle are considered in the definition of herd infection status. In general, protocols analyzed in this review suffered from very low sensitivities, which hardly justifies their use as part of disease surveillance as single testing. Nevertheless, test sensitivity can be increased by the adoption of more inclusive definitions of disease-free herds. Further, low-sensitivity and high-specificity methods can be valuable tools for surveillance when used repeatedly over time. [ABSTRACT FROM AUTHOR]

The chronic nature of Jhone's disease and prolonged incubation period of the agent often complicate the diagnosis of this disease. The present study was undertaken with the objective to compare fecal microscopy using Ziehl-Nielsen (ZN) staining method and Polymerase Chain Reaction assay for detection of Mycobacterium avium subspecies paratuberculosis (MAP) in small ruminants. A total of 205 fecal samples of sheep and goat were first microscopically examined using ZN staining method and later tested for presence of MAP DNA through IS900 PCR. Win Episcope 2.0 software was used to determine agreement between the test assays. Of the total 205 fecal samples, 78 (38.0%) were positive by ZN staining method and 48 (23.4%) by IS900 PCR. Moderate level of agreement (0.517) was observed between the test assays. Restriction enzyme analysis of DNA amplicons from IS1311 PCR revealed that all positive samples belonged to Bison type MAP strain. Single predominant strain (Bison type) among all ruminants indicates its ability to infect multiple host species, possibility of interspecies transmission and endemic co-circulation. [ABSTRACT FROM AUTHOR]

Not only are many Mycobacteria pathogens, but they can act as strong non‐specific immunopotentiators, generating beneficial effects on the pathogenesis of some diseases. However, there has been no direct evidence of the effect of mycobacterial species on colorectal cancer (CRC). Herein, we showed that there may be a meaningful inverse correlation between the incidence of tuberculosis and CRC based on global statistics and that heat‐killed Mycobacterial tuberculosis and live Mycobacterium bovis (Bacillus Calmette–Guérin strain) could ameliorate CRC development. In particular, using a faecal microbiota transplantation and a comparison between separate housing and cohousing, we demonstrated that the gut microbiota is involved in the protective effects. The microbial alterations can be elucidated by the modulation of antimicrobial activities including those of the Reg3 family genes. Furthermore, interleukin‐22 production by T helper cells contributed to the anti‐inflammatory activity of Mycobacteria. Our results revealed a novel role of Mycobacteria involving gut microbial alterations in dampening inflammation‐associated CRC and an immunological mechanism underlying the interaction between microbes and host immunity. [ABSTRACT FROM AUTHOR]

Non-tuberculous mycobacteria (NTM) infection has increasingly been reported throughout the world, especially in Asia. Autoantibodies to interferon-γ are implicated in the pathogenesis of adult-onset immunodeficiency resulting in multiple opportunistic infections, in particular NTM infection. There are few reports regarding Mycobacterium avium complex infection of the nasal cavity or parotid gland in this condition. The authors reported the first case of nasal and parotid Mycobacterium avium complex presenting with recurrent epistaxis, nasal mass, and parotitis successfully treated with combined systemic and topical anti-mycobacterial agents in Thailand. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis and Mycobacterium avium subsp. paratuberculosis, respectively the causative agents of bovine tuberculosis (bTB) and bovine paratuberculosis (PTB), share a high number of antigenic proteins. This characteristics makes the differential diagnosis of the diseases difficult. The interferon gamma (IFN-γ), C-X-C motif chemokine ligand 10 (CXCL10), matrix metallopeptidase 9 (MMP9), interleukin 22 (IL-22) and thrombospondin 1 (THBS1) bovine genes have already been shown to be accurate transcriptional biomarkers of bTB. In order to improve the diagnosis of bTB and PTB, in the present study we evaluated the risk of false positivity of these bTB biomarkers in cattle with PTB. The transcription of these genes was studied in 13 PTB-infected cattle, using Mycobacterium avium subsp. paratuberculosis (MAP)-stimulated peripheral blood mononuclear cells (PBMC). Overall, the levels of IFN-γ, CXCL10, MMP9 and IL-22 transcripts in MAP-stimulated PBMC failed to differentiate animals with PTB from healthy animals. However, as bTB-afflicted cattle do, the MAP-infected group also displayed a lower level of THBS1 transcription than the non-infected animals. The results of this study add new specificity attributes to the levels of transcription of IFN-γ, CXCL10, MMP9 and IL-22 as biomarkers for bTB. [ABSTRACT FROM AUTHOR]

Crohn’s disease (CD) is a multifactorial chronic disorder that involves a combination of factors, including genetics, immune response, and gut microbiota. Therapy includes salicylates, immunosuppressive agents, corticosteroids, and biologic drugs. International guidelines do not recommend the use of antibiotics for CD patients, except in the case of septic complications. Increasing evidence of the involvement of gut bacteria in this chronic disease supports the rationale for using antibiotics as the primary treatment for active CD. In recent decades, several pathogens have been reported to be involved in the development of CD, but only Escherichia coli (E. coli) and Mycobacterium avium paratubercolosis (MAP) have aroused interest due to their strong association with CD pathogenesis. Several meta-analyses have been published concerning antibiotic treatment for CD patients, but randomized trials testing antibiotic treatment against E. coli and MAP have not shown prolonged benefits and have generated conflicting results; several questions are still unresolved regarding trial design, antibiotic dosing, the formulation used, the treatment course, and the outcome measures. In this paper, we provide an overview and update of the trials testing antibiotic treatment for active CD patients, taking into account the role of pathogens, the mechanisms by which different antibiotics act on harmful pathogens, and antibiotic resistance. Finally, we also present new lines of study for the future regarding the use of antibiotics to treat patients with active CD.

This article discusses the potential association between Crohn's disease (CD) and Mycobacterium avium ssp. paratuberculosis (MAP), a bacterium that causes Johne's disease in ruminants. The article highlights the challenges in detecting MAP and its ability to evade the host's immune system. It also reviews evidence for the pro-inflammatory properties of MAP and its similarities to other mycobacterial infections. The article suggests that improved detection methods could help determine the role of MAP in CD and potentially lead to targeted therapy. However, it acknowledges that other environmental factors may also contribute to the development of both diseases. [Extracted from the article]

This document is a corrigendum published in the journal Frontiers in Immunology. It corrects an error in the affiliation of one of the authors, Gerard Badia-Bringue. The correction adds an additional affiliation to his name. The authors apologize for the error and state that it does not affect the scientific conclusions of the article. The original article has been updated accordingly. The document also includes information about the publication date, citation, and copyright information. [Extracted from the article]

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease, a chronic emaciating disease of ruminants that causes enormous economic losses to the bovine industry, globally. However, there are still remaining clues to be solved in the pathogenesis and diagnosis of the disease. Therefore, an in vivo murine experimental model was tried to understand responses in early stage of MAP infection by oral and intraperitoneal (IP) routes. In the MAP infection size, and weight of spleen and liver were increased in the IP group compared with oral groups. Severe histopathological changes were also observed in the spleen and liver of IP infected mice at 12 weeks post-infection (PI). Acid-fast bacterial burden in the organs was closely related to histopathological lesions. In the cytokine production from splenocytes of MAP-infected mice, higher amounts of in TNF-α, IL-10, and IFN-γ were produced at early stage of IP-infected mice while IL-17 production was different at time and infected groups. This phenomenon may indicate the immune shift from Th1 to Th17 through the time course of MAP infection. Systemic and local responses in the MAP-infection were analyzed by using transcriptomic analysis in the spleens and mesenteric lymph nodes (MLN). Based on the analysis of biological processes at 6 weeks PI in spleen and MLN in each infection group, canonical pathways were analyzed with ingenuity pathway analysis in the immune responses and metabolism especially lipid metabolism. Infected host cells with MAP increased in the production of proinflammatory cytokines and reduced the availability of glucose at early stage of infection (p < 0.05). Also, host cells secreted cholesterol through cholesterol efflux to disturb energy source of MAP. These results reveal immunopathological and metabolic responses in the early stage of MAP infection through the development of a murine model. [ABSTRACT FROM AUTHOR]

Simple Summary: Transmission of Mycobacterium avium subspecies paratuberculosis (MAP) from infected adult cattle to susceptible calves occurs mainly through contamination of the calf environment, i.e., the calving pen and the pre-weaned calf rearing area, with adult faeces. Control programmes for Johne's disease utilise a risk assessment and management plan (RAMP) to evaluate the risk of transmission of infection on a specific farm, however the assessment is limited by its subjective, point-in-time nature. The objective of this study was to evaluate a novel environmental sampling protocol for measurement of MAP contamination of the calf environment on infected farms. Across 28 infected farms, 46% had detectable MAP in the calf environment, with 21% of farms having detectable MAP in the pre-weaned calf area. There was no significant association found between the RAMP scores for each farm and the result of environmental testing for MAP, and there was a moderate correlation found between RAMP scores and the level of MAP contamination as quantified by PCR. We conclude that environmental sampling is a potentially useful tool to objectively measure transmission risk in the calf environment on farms, as a complement to the annual RAMP. One of the pillars of Johne's disease control is to break the cycle of transmission from infectious adult animals to young susceptible animals. Many control programmes utilise a risk assessment and management plan (RAMP) to identify specific risks for transmission of infection on individual farms and then recommend tailored biosecurity measures to mitigate the risk. It is important that infected farms in particular, practice effective biocontainment in the calving area and pre-weaned calf area. The objectives of this study were: (1) to determine what proportion of MAP-infected farms (PCR-positive) enrolled in a control programme had detectable MAP in their calf environment; (2) to compare RAMP scores and apparent within-herd prevalence (aWHP) of PCR-positive and PCR-negative farms; (3) to evaluate the correlation between RAMP scores, aWHP and levels of contamination based on PCR test Ct value. A novel environmental sampling protocol combining manure samples and boot swab samples was conducted in the calving area and pre-weaned calf area on 28 dairy farms with PCR-confirmed MAP infection. All samples were tested with PCR. Logistic regression modelling was used to evaluate the association between RAMP score and aWHP and PCR outcome. Overall, 46% of farms had positive PCR samples in either the calving area, pre-weaned calf area or both. The calving area was positive in 36% of farms and the pre-weaned calf area was positive in 21% of farms. There was a moderate, negative correlation (r = −0.45; p = 0.08) observed between RAMP scores and Ct value at the sample-level that slightly missed the required significance level. No significant association was identified between RAMP scores or aWHP and PCR test outcome (positive or negative). It was concluded that environmental sampling of the calving area and pre-weaned calf area has potential applications in the assessment of transmission risk on infected farms and could be used to monitor the efficacy of biosecurity measures over time. Further research conducted on a larger scale is required to support these results. [ABSTRACT FROM AUTHOR]

Simple Summary: Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis (PTB), chronic enteritis of ruminants spread worldwide. PTB is, by now, considered a conditioned disease, depending on both environmental and genomic factors. PTB susceptibility seems to be related to some genes coding for immune regulators involved in the cell-mediated response during infection: genetic markers, particularly single nucleotide polymorphisms (SNPs), have been investigated in several studies, and different candidate genes have been highlighted as associated with PTB resistance/susceptibility. The aim of this preliminary study was to verify, for the first time in a local beef cattle breed, known as Marchigiana, an association between MAP infection status and SNPs in candidate immune-genes. Specifically, in a MAP-infected herd, IFN-γ tests, ELISA, qPCR, and cultures were performed, for a follow-up range of 3–6 years, on 112 bovines to evaluate the state of MAP infection. Animals with positive results for at least one test were considered infected. DNA samples of bovines with a known MAP status were analyzed to assess the presence and the genotypic frequency of SNPs in genes encoding for gamma-interferon (BoIFNG), interleukin receptor 10 (IL10RA), interleukin receptor 12 (IL12RB2), and toll-like receptors (TLR1, TLR2, TLR4). For the IL10RA and IL12RB2 genes, relevant differences in genotypic frequencies among the considered cattle groups were observed. For all the investigated candidate genes, SNP genotypes that have been associated with PTB resistance in the literature, were found more frequently, suggesting potential genetic resistance traits in the Marchigiana breed. Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis (PTB), a widespread chronic enteritis of ruminants. The progression of the infection depends on the containment action of innate and cell-mediated immunity (CMI), and it is related to environmental and genetic factors. In particular, PTB susceptibility seems to be associated with specific genes coding for immune regulators involved in the cell-mediated response during the infection. The aim of this preliminary study was to verify, in Italian beef cattle, an association between MAP infectious status and the presence of single nucleotide polymorphisms (SNPs) in candidate genes. To the best of our knowledge, this is the first investigation conducted on a native beef cattle breed, known as Marchigiana, reared in Central Italy. The present research, based on a longitudinal study, aimed to identify and correlate phenotypic and genetic profiles characteristic of the subjects potentially able to contrast or contain PTB. In a MAP-infected herd, ELISA, IFN-γ tests, qPCR, and cultures were performed at a follow-up, occurring within a period ranging from three to six years, to evaluate the individual state of infection. Animals testing positive for at least one test were considered infected. DNA samples of 112 bovines, with known MAP statuses, were analyzed to verify an association with SNPs in the genes encoding gamma-interferon (BoIFNG), interleukin receptor 10 (IL10RA), interleukin receptor 12 (IL12RB2), and toll-like receptors (TLR1, TLR2, TLR4). Regarding statistical analysis, the differences among target genes and pairs of alleles in the analyzed groups of animals, were evaluated at a significance level of p < 0.05. For IL10RA and for IL12RB2 genes, relevant differences in genotypic frequencies among the considered cattle groups were observed. For all candidate genes studied in this investigation, SNP genotypes already associated with PTB resistance were found more frequently in our population, suggesting potential resistance traits in the Marchigiana breed. [ABSTRACT FROM AUTHOR]

Johne's disease (JD) control is often based on the culling of positive animals and the adoption of management practices that minimize exposure of young stock to the pathogen (Mycobacterium avium ssp. paratuberculosis). Throughout 2010 to 2013, the province of Ontario, Canada, instituted a voluntary Johne's control program consisting of whole-herd testing and risk assessment. The JD risk assessment evaluated 5 management areas to characterize herd JD risk. Using a modified milk ELISA technique with an optical density cut-off of 0.089, province-wide bulk tank milk (BTM) testing was used to assess the prevalence of JD high-risk herds at the end of the control program and again 4 yr after its completion. Approximately 71% of Ontario bulk tanks were classified as positive in 2017 compared with roughly 46% in 2013. In 2019, the same JD risk assessment used in the original program was readministered on 180 Ontario dairy farms. Using this cross-sectional approach, logistic regression models were built using data from the original program risk assessment and follow-up risk assessment as well as the BTM ELISA results to determine management factors associated with the control of JD. We demonstrated that management of the maternity area is an important factor in the control of Johne's disease. Although it is believed that the highest risk group for JD infection is calves under 6 mo, the cleanliness scores of older heifers and their exposure to mature cow manure was significantly associated with JD control; farms with highly contaminated weaned and bred heifers and those that had exposure to mature cow manure were more likely to be unsuccessful in their JD control efforts. Careful management of young calves appears to be important for JD control, and this management should continue even after calves have left the maternity area. [ABSTRACT FROM AUTHOR]

Slowly growing nontuberculous mycobacteria (NTM) comprise a diverse group of environmental organisms, many of which are important human pathogens. The most common and well-known member of this group is Mycobacterium avium , the leading cause of nontuberculous mycobacterial pulmonary disease (NTM-PD) globally. This review focuses on the less common, but notable, species of slowly growing NTM with respect to lung disease. To prepare this article, literature searches were performed using each species name as the key word. Society guidelines were consulted, and relevant articles also were identified through the reference lists of key articles. The specific organisms highlighted include Mycobacterium kansasii , Mycobacterium xenopi , Mycobacterium malmoense , Mycobacterium simiae, and Mycobacterium szulgai. Although these organisms are closely related, they have distinct epidemiologic features and behavior as pathogens. Therefore, the diagnosis and management of NTM-PD require a nuanced approach that takes into consideration the unique characteristics of each species. There is limited evidence to inform the optimal treatment of NTM-PD. Antimicrobial therapy is often challenging because of the presence of drug resistance and few antibiotic options. Regimen selection should generally be guided by drug susceptibility testing, although the correlation between clinical outcomes and in vitro susceptibility thresholds has not been defined for most species. [ABSTRACT FROM AUTHOR]

Mycobacterium avium ssp. paratuberculosis (MAP), causes Johne's disease (JD), or paratuberculosis, a chronic enteritis of ruminants, which in goats is characterized by ileal lesions. The work described here is a case–control association study using the Illumina Caprine SNP50 BeadChip to unravel the genes involved in susceptibility of goats to JD. Goats in herds with a high occurrence of Johne's disease were classified as healthy or infected based on the level of serum antibodies against MAP, and 331 animals were selected for the association study. Goats belonged to the Jonica (157) and Siriana breeds (174). Whole‐genome association analysis identified one region suggestive of significance associated with an antibody response to MAP on chromosome 7 (p‐value = 1.23 × 10−5). These results provide evidence for genetic loci involved in the antibody response to MAP in goats. [ABSTRACT FROM AUTHOR]

Amplification of the IS900 multicopy element is a hallmark nucleic acid-based diagnostic test for Mycobacterium avium subsp. paratuberculosis, which causes Johne's disease in ruminants. This assay is frequently used to determine the presence of the bacterium in feces of infected cattle and sheep. Two IS900 primer sets developed in the 1990s were widely used for decades, and their use has continued in current studies. However, these primers were developed prior to the availability of complete genome sequences. Recent sequence analysis of the binding locations for one primer pair (P90/ P91) identified errors and binding inefficiencies that can be easily corrected to further increase detection sensitivity. The P90 primer is missing two nucleotides that should be present near the 39 end, and it does not bind all copies of IS900 due to 59 deletions at some IS900 loci. These IS900 primer pairs, along with newly developed primers, were tested by real-time PCR on purified genomic DNA to determine which primer set performed the best and how primer design errors affect amplification efficiencies. The newly designed PCR primer set (JB5) showed increased sensitivity by two to three quantification cycles using purified genomic DNA and was similar in efficiency to 150C/ 921. These tests were extended using DNA from feces and tissues of infected cows, which showed similar results. Finally, a 167-bp partial duplication of IS900 was found in type I strains. Although P90 and P91 primers successfully amplify M. avium subsp. paratuberculosis DNA, their use should be discontinued in favor of more efficient primer pairs in future studies. [ABSTRACT FROM AUTHOR]

Purpose: Heterozygous dominant-negative (DN) STAT1 variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan. Methods: An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells. Results: Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by Mycobacterium bovis bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in STAT1, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT STAT1. Conclusion: Four kindred MSMD subjects with 3 novel variants and 1 known variant in STAT1 were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD. [ABSTRACT FROM AUTHOR]

Mycobacterium avium subsp. paratuberculosis (MAP) is the pathogen responsible for paratuberculosis or Johne's Disease (JD) in ruminants, which is responsible for substantial economic losses worldwide. MAP transmission primarily occurs through the fecal-oral route, and the introduction of an MAP infected animal into a herd is an important transmission route. In the current study, we characterized MAP isolates from 67 cows identified in 20 herds from the provinces of Quebec and Ontario, Canada. Whole genome sequencing (WGS) was performed and an average genome coverage (relative to K-10) of ~14.9 fold was achieved. The total number of SNPs present in each isolate varied from 51 to 132 and differed significantly between herds. Isolates with the highest genetic variability were generally present in herds from Quebec. The isolates were broadly separated into two main clades and this distinction was not influenced by the province from which they originated. Analysis of 8 MIRU-VNTR loci and 11 SSR loci was performed on the 67 isolates from the 20 dairy herds and publicly available references, notably major genetic lineages and six isolates from the province of Newfoundland and Labrador. All 67 field isolates were phylogenetically classified as Type II (C-type) and according toMIRU-VNTR, the predominant typewas INMV 2 (76.1%) among four distinct patterns. Multilocus SSR typing identified 49 distinct INMV SSR patterns. The discriminatory index of the multilocus SSR typing was 0.9846, which was much higher than MIRU-VNTR typing (0.3740). Although multilocus SSR analysis provides good discriminatory power, the resolution was not informative enough to determine inter-herd transmission. In select cases, SNP-based analysis was the only approach able to document disease transmission between herds, further validated by animal movement data. The presence of SNPs in several virulence genes, notably for PE, PPE, mce and mmpL, is expected to explain differential antigenic or pathogenetic host responses. SNP-based studies will provide insight into how MAP genetic variation may impact host-pathogen interactions. Our study highlights the informative power of WGS which is now recommended for epidemiological studies and to document mixed genotypes infections. [ABSTRACT FROM AUTHOR]