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Background: Human papillomavirus (HPV) serodynamics following infection has never been evaluated prospectively among women living with HIV (WLHIV). We determined HPV seroprevalence, seroconversion, and cervical HPV-DNA acquisition among WLHIV.Methods: Prospective study of 604 WLHIV in Johannesburg, South Africa aged 25-50 years. At baseline and 16 months (endline), HPV type-specific antibodies (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) were measured using HPV-pseudovirions and cervical HPV-DNA genotypes using INNO-LiPA.Results: Seroprevalence of any-HPV was 93.2% and simultaneous seropositivity for HPV types of the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 21.4%, 10.9%, and 2.8%. Among 219 women with cervical HPV-DNA, same-type seronegative and without high-grade cervical intraepithelial neoplasia at baseline, 51 (23.3%) had type-specific seroconversion at endline. Risk of type-specific seroconversion was higher among recent antiretroviral therapy users (ART ≤2 years vs ART naive: adjusted OR [aOR] = 2.39; 95% CI, 1.02-5.62), and lower among women with low CD4+ at endline (≤350 vs >350 cells/mm3: aOR = 0.51; 95% CI, 0.24-1.07). Risk of cervical HPV-DNA acquisition was lower in women seropositive for HPV18, 35, and 58 at baseline.Conclusion: WLHIV have evidence of seroconversion in response to baseline HPV-DNA, dependent on CD4+ count and ART. Baseline HPV seropositivity confers limited protection against some HPV types. [ABSTRACT FROM AUTHOR]

Background: HVTN 505 was a human immunodeficiency virus type 1 (HIV-1) preventive vaccine efficacy trial of a DNA/recombinant adenovirus serotype 5 (rAd5) vaccine regimen. We assessed antibody responses measured 1 month after final vaccination (month 7) as correlates of HIV-1 acquisition risk.Methods: Binding antibody responses were quantified in serum samples from 25 primary endpoint vaccine cases (diagnosed with HIV-1 infection between month 7 and month 24) and 125 randomly sampled frequency-matched vaccine controls (HIV-1 negative at month 24). We prespecified for a primary analysis tier 6 antibody response biomarkers that measure immunoglobulin G (IgG) and immunoglobulin A (IgA) binding to Env proteins and 2 previously assessed T-cell response biomarkers.Results: Envelope-specific IgG responses were significantly correlated with decreased HIV-1 risk. Moreover, the interaction of IgG responses and Env-specific CD8+ T-cell polyfunctionality score had a highly significant association with HIV-1 risk after adjustment for multiple comparisons.Conclusions: Vaccinees with higher levels of Env IgG have significantly decreased HIV-1 risk when CD8+ T-cell responses are low. Moreover, vaccinees with high CD8+ T-cell responses generally have low risk, and those with low CD8+ T-cell and low Env antibody responses have high risk. These findings suggest the critical importance of inducing a robust IgG Env response when the CD8+ T-cell response is low. [ABSTRACT FROM AUTHOR]

Background: In the current study, we determined the effects of interleukin (IL)-21 on human natural killer (NK) cells and monocyte responses during Mycobacterium tuberculosis (Mtb) infection.Methods: We found that Mtb stimulated CD4+ and NK T cells from healthy individuals with latent tuberculosis infection (LTBI+) are major sources of IL-21. CD4+ cells from tuberculosis patients secreted less IL-21 than did CD4+ cells from healthy LTBI+ individuals. Interleukin-21 had no direct effect on Mtb-stimulated monocytes.Results: Interleukin-21-activated NK cells produced interferon (IFN)-γ, perforin, granzyme B, and granulysin; lysed Mtb-infected monocytes; and reduced Mtb growth. Interleukin-21-activated NK cells also enhanced IL-1β, IL-18, and CCL4/macrophage-inflammatory protein (MIP)-1β production and reduced IL-10 production by Mtb-stimulated monocytes. Recombinant IL-21 (1) inhibited Mtb growth, (2) enhanced IFN-γ, IL-1β, IL-18, and MIP-1β, and (3) reduced IL-10 expression in the lungs of Mtb-infected Rag2 knockout mice.Conclusions: These findings suggest that activated T cells enhance NK cell responses to lyse Mtb-infected human monocytes and restrict Mtb growth in monocytes through IL-21 production. Interleukin-21-activated NK cells also enhance the immune response by augmenting IL-1β, IL-18, and MIP-1β production and reducing IL-10 production by monocytes in response to an intracellular pathogen. [ABSTRACT FROM AUTHOR]

We studied the relationship between varicella-zoster virus (VZV) DNAemia and development of VZV-specific immunity after administration of live-attenuated zoster vaccine. VZV-DNAemia, detected by polymerase chain reaction (PCR), and VZV-specific effector (Teff) and memory (Tmem) T cells, was measured in 67 vaccinees. PCR was positive in 56% (9 direct, 28 nested) on day 1 and in 16% (1 direct, 10 nested) on day 14. Teff progressively increased in direct-PCR-positive vaccinees up to day 30, but Tmem did not. Conversely, Tmem, but not Teff, increased in direct-PCR-negative vaccinees on day 7. The kinetics of these immune responses and VZV DNAemia suggested that direct-PCR sample positive represented viremia. [ABSTRACT FROM AUTHOR]

Background: The ability of Staphylococcus aureus to evade killing by human neutrophils significantly contributes to disease progression. In this study, we characterize an influential role for the S. aureus SaeR/S 2-component gene regulatory system in suppressing monocyte production of tumor necrosis factor alpha (TNF-α) to subsequently influence human neutrophil priming.Methods: Using flow cytometry and TNF-α specific enzyme-linked immunosorbent assays we identify the primary cellular source of TNF-α in human blood and in purified peripheral blood mononuclear cells (PBMCs) during interaction with USA300 and an isogenic saeR/S deletion mutant (USA300∆saeR/S). Assays with conditioned media from USA300 and USA300∆saeR/S exposed PBMCs were used to investigate priming on neutrophil bactericidal activity.Results: TNF-α production from monocytes was significantly reduced following challenge with USA300 compared to USA300∆saeR/S. We observed that priming of neutrophils using conditioned medium from peripheral blood mononuclear cells stimulated with USA300∆saeR/S significantly increased neutrophil bactericidal activity against USA300 relative to unprimed neutrophils and neutrophils primed with USA300 conditioned medium. The increased neutrophil bactericidal activity was associated with enhanced reactive oxygen species production that was significantly influenced by elevated TNF-α concentrations.Conclusions: Our findings identify an immune evasion strategy used by S. aureus to impede neutrophil priming and subsequent bactericidal activity. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus and Pseudomonas aeruginosa are key bacterial pathogens of the respiratory tract in patients with cystic fibrosis (CF). Although P. aeruginosa chronic bronchial infection is associated with a poorer prognosis, the consequences of S. aureus colonization on CF outcomes are controversial.Methods: In this paper, murine models of infection resembling traits of the CF human airways disease have been revisited using an infection schedule that mimics the sequence of events of pulmonary disease in CF patients. First, mice were infected with S. aureus, embedded in agar beads; this was followed by P. aeruginosa infection and analysis of bacterial load, leukocyte infiltration, and lung tissue damage.Results: We reveal that (1) S. aureus promotes severe lesions including abscess formation, (2) S. aureus increases the risk of subsequent chronic P. aeruginosa respiratory infection, and (3) once the chronic infection has been established, P. aeruginosa influences most of the inflammatory responses independent of S. aureus.Conclusions: Our findings established the significance of S. aureus colonization per se and the impact on the subsequent P. aeruginosa infection. This would point towards a thorough assessment for the need of treatment against S. aureus. [ABSTRACT FROM AUTHOR]

Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1-infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Background: Controlling hepatitis C virus (HCV) transmission among people who inject drugs (PWID) has focused on preventing sharing syringes and drug preparation paraphernalia, but it is unclear whether HCV incidence linked to sharing paraphernalia reflects contamination of the paraphernalia or syringe-mediated contamination when drugs are shared.Methods: In experiments designed to replicate real-world injection practices when drugs are shared, the residual contents of HCV-contaminated syringes with detachable or fixed needled were passed through the "cookers" and filters used by PWID in preparing drugs for injection and then introduced into a second syringe. All items were tested for the presence of infectious HCV using a chimeric HCV with a luciferase gene.Results: Hepatitis C virus could not be recovered from cookers regardless of input syringe type or cooker design. Recovery was higher when comparing detachable needles to fixed needles for residue in input syringes (73.8% vs 0%), filters (15.4% vs 1.4%), and receptive syringes (93.8% vs 45.7%).Conclusions: Our results, consistent with the hypothesis that sharing paraphernalia does not directly result in HCV transmission but is a surrogate for transmissions resulting from sharing drugs, have important implications for HCV prevention efforts and programs that provide education and safe injection supplies for PWID populations. [ABSTRACT FROM AUTHOR]

Background: Data on how respiratory syncytial virus (RSV) genotypes influence disease severity and host immune responses is limited. Here, we characterized the genetic variability of RSV during 5 seasons, and evaluated the role of RSV subtypes, genotypes, and viral loads in disease severity and host transcriptional profiles.Methods: A prospective, observational study was carried out, including a convenience sample of healthy infants hospitalized with RSV bronchiolitis. Nasopharyngeal samples for viral load quantitation, typing, and genotyping, and blood samples for transcriptome analyses were obtained within 24 hours of hospitalization. Multivariate models were constructed to identify virologic and clinical variables predictive of clinical outcomes.Results: We enrolled 253 infants (median age 2.1 [25%-75% interquartile range] months). RSV A infections predominated over RSV B and showed greater genotype variability. RSV A/GA2, A/GA5, and RSV B/BA were the most common genotypes identified. Compared to GA2 or BA, infants with GA5 infections had higher viral loads. GA5 infections were associated with longer hospital stay, and with less activation of interferon and increased overexpression of neutrophil genes.Conclusions: RSV A infections were more frequent than RSV B, and displayed greater variability. GA5 infections were associated with enhanced disease severity and distinct host immune responses. [ABSTRACT FROM AUTHOR]

Clostridium perfringens enterotoxin (CPE) causes food poisoning and antibiotic-associated diarrhea. It uses some claudin tight junction proteins (eg, claudin-4) as receptors to form Ca2+-permeable pores in the membrane, damaging epithelial cells in small intestine and colon. We demonstrate that only a subpopulation of colonic enterocytes which are characterized by apical dislocation of claudins are CPE-susceptible. CPE-mediated damage was enhanced if paracellular barrier was impaired by Ca2+ depletion, proinflammatory cytokine tumor necrosis factor a, or dedifferentiation. Microscopy, Ca2+ monitoring, and electrophysiological data showed that CPE-mediated cytotoxicity and barrier disruption was limited by extent of CPE-binding. The latter was restricted by accessibility of non-junctional claudin molecules such as claudin-4 at apical membranes. Focal-leaks detected in HT-29/B6 colonic monolayers were verified for native tissue using colon biopsies. These mechanistic findings indicate how CPE-mediated effects may turn from self-limiting diarrhea into severe clinical manifestation such as colonic necrosis--if intestinal barrier dysfunction, eg, during inflammation facilitates claudin accessibility. [ABSTRACT FROM AUTHOR]

Background: The most common clinical manifestation of early Lyme disease is the erythema migrans (EM) skin lesion that develops at the tick bite site typically between 7 and 14 days after infection with Borreliella burgdorferi. The host-pathogen interactions that occur in the skin may have a critical role in determining outcome of infection.Methods: Gene arrays were used to characterize the global transcriptional alterations in skin biopsy samples of EM lesions from untreated adult patients with Lyme disease in comparison to controls.Results: The transcriptional pattern in EM biopsies consisted of 254 differentially regulated genes (180 induced and 74 repressed) characterized by the induction of chemokines, cytokines, Toll-like receptors, antimicrobial peptides, monocytoid cell activation markers, and numerous genes annotated as interferon (IFN)-inducible. The IFN-inducible genes included 3 transcripts involved in tryptophan catabolism (IDO1, KMO, KYNU) that play a pivotal role in immune evasion by certain other microbial pathogens by driving the differentiation of regulatory T cells.Conclusions: This is the first study to globally assess the human skin transcriptional response during early Lyme disease. Borreliella burgdorferi elicits a predominant IFN signature in the EM lesion, suggesting a potential mechanism for spirochetal dissemination via IDO1-mediated localized immunosuppression. [ABSTRACT FROM AUTHOR]

Background: Most insights into the cascade of immune events after acute respiratory syncytial virus (RSV) infection have been obtained from animal experiments or in vitro models.Methods: In this study, we investigated host gene expression profiles in nasopharyngeal (NP) swabs and whole blood samples during natural RSV and rhinovirus (hRV) infection (acute versus early recovery phase) in 83 hospitalized patients <2 years old with lower respiratory tract infections.Results: Respiratory syncytial virus infection induced strong and persistent innate immune responses including interferon signaling and pathways related to chemokine/cytokine signaling in both compartments. Interferon-α/β, NOTCH1 signaling pathways and potential biomarkers HIST1H4E, IL7R, ISG15 in NP samples, or BCL6, HIST2H2AC, CCNA1 in blood are leading pathways and hub genes that were associated with both RSV load and severity. The observed RSV-induced gene expression patterns did not differ significantly in NP swab and blood specimens. In contrast, hRV infection did not as strongly induce expression of innate immunity pathways, and significant differences were observed between NP swab and blood specimens.Conclusions: We conclude that RSV induced strong and persistent innate immune responses and that RSV severity may be related to development of T follicular helper cells and antiviral inflammatory sequelae derived from high activation of BCL6. [ABSTRACT FROM AUTHOR]

Background: Bone loss occurs in human immunodeficiency virus (HIV) infection but paradoxically is intensified by HIV-associated antiretroviral therapy (ART), resulting in an increased fracture incidence that is largely independent of ART regimen. Inflammation in the bone microenvironment associated with T-cell repopulation following ART initiation may explain ART-induced bone loss. Indeed, we have reported that reconstitution of CD3+ T cells in immunodeficient mice mimics ART-induced bone loss observed in humans. In this study, we quantified the relative effects of CD4+ and CD8+ T-cell subsets on bone.Methods: T-cell subsets in T-cell receptor β knockout mice were reconstituted by adoptive transfer with CD4+ or CD8+ T-cells subsets were reconstituted in T-cell receptor β knockout mice by adoptive transfer, and bone turnover, bone mineral density, and indices of bone structure and turnover were quantified.Results: Repopulating CD4+ but not CD8+ T cells significantly diminished bone mineral density. However, micro-computed tomography revealed robust deterioration of trabecular bone volume by both subsets, while CD4+ T cells additionally induced cortical bone loss.Conclusions: CD4+ T-cell reconstitution, a key function of ART, causes significant cortical and trabecular bone loss. CD8+ T cells may further contribute to trabecular bone loss in some patients with advanced AIDS, in whom CD8+ T cells may also be depleted. Our data suggest that bone densitometry used for assessment of the condition of bone in humans may significantly underestimate trabecular bone damage sustained by ART. [ABSTRACT FROM AUTHOR]

Background: Norovirus is the leading cause of community-acquired and nosocomial acute gastroenteritis. Routine testing for norovirus is seldom undertaken, and diagnosis is mainly based on presenting symptoms. This makes understanding the burden of medically attended norovirus-attributable gastroenteritis (MA-NGE) and targeting care and prevention strategies challenging.Methods: We used linked population-based healthcare datasets (Clinical Practice Research Datalink General Practice OnLine Database linked with Hospital Episode Statistics Admitted Patient Care) to model the incidence of MA-NGE associated with primary care consultations or hospitalizations according to age groups in England in the period July 2007-June 2013.Results: Mean annual incidence rates of MA-NGE were 4.9/1000 person-years and 0.7/1000 person-years for episodes involving primary care or hospitalizations, respectively. Incidence rates were highest in children aged <5 years: 34.0 consultations/1000 person-years and 3.3 hospitalizations/1000 person-years. Medically attended norovirus-attributable gastroenteritis hospitalization rates were second highest in adults aged >65 years (1.7/1000 person-years).Conclusions: In this particular study, the burden of MA-NGE estimated from healthcare datasets was higher than previously estimated in small cohort studies in England. Routinely collected primary care and hospitalization datasets are useful resources to estimate and monitor the burden of MA-NGE in a population over time. [ABSTRACT FROM AUTHOR]

Background: Recent evidence indicates a robust competition between the host and mycobacteria for iron acquisition during mycobacterial infection. Variable effects of iron supplementation on the susceptibility to mycobacterial infection have been reported. In this study, we revisited the effects of an experimental iron-enriched diet on Mycobacterium bovis bacille Calmette-Guerin (BCG) infection.Methods: Mice fed a standard diet or a diet moderately enriched with iron were infected with M. bovis BCG expressing green fluorescent protein. Colony-forming unit numbers, host myeloid cell counts, cell recruitment, cytokine production, and iron gene expression were determined at different stages of infection. Bone marrow-derived macrophages incubated with or without iron were also used to measure bacterial uptake, levels of inflammation markers, and iron gene expression.Results: In vivo analysis of BCG-infected mice revealed that moderate iron supplementation reduced inflammation, as measured by decreased proinflammatory cytokine levels and neutrophil recruitment and enhanced T-cell recruitment in granulomas, and decreased the bacterial load. Enhanced bacterial clearance in the liver correlated with upregulation of the gene encoding hepcidin, which is known to have antimicrobial proprieties, and with sequestration of iron in tissues. In cultured macrophages, iron supplementation induced reactive oxygen species and reduced uptake and intracellular growth of BCG.Conclusion: Moderate iron diet supplementation diminished inflammation and growth of M. bovis BCG via enhanced reactive oxygen species production, immune cell activation, and local hepcidin expression. [ABSTRACT FROM AUTHOR]

Background: Human herpesvirus 8 (HHV-8) infection occurs in early childhood and is associated with human immunodeficiency virus type 1 (HIV-1) infection and risk for Kaposi sarcoma, but behaviors associated with HHV-8 transmission are not well described.Methods: We enrolled and followed a prospective cohort of 270 children and their household members to investigate risk factors for HHV-8 transmission in Lusaka, Zambia.Results: We report an incidence of 30.07 seroconversions per 100 child-years. Independent risk factors for HHV-8 incident infection included having a child who shared utensils with a primary caregiver (hazards ratio [HR], 2.33; 95% confidence interval [CI], 1.49-7.14), having an increasing number of HHV-8-infected household members (HR, 1.27; 95% CI, 1.09-2.79), and having ≥5 siblings/children in the household (HR, 2.24; 95% CI, 1.03-4.88). Playing with >5 children a day was protective against infection (HR, 0.54; 95% CI, .33-0.89), as was increasing child age (HR, 0.96; 95% CI, .93-.99).Conclusions: This is the first study to find a temporal association between limited child feeding behaviors and risk for HHV-8 infection. Child food- and drink-sharing behaviors should be included in efforts to minimize HHV-8 transmission, and households with a large number of siblings should receive additional counseling as childhood infections occur in the home context. [ABSTRACT FROM AUTHOR]

H7 subtype influenza viruses represent a persistent public health threat because of their continued detection in poultry and ability to cause human infection. An outbreak of highly pathogenic avian influenza H7N7 virus in Italy during 2013 resulted in 3 cases of human conjunctivitis. We determined the pathogenicity and transmissibility of influenza A/Italy/3/2013 virus in mouse and ferret models and examined the replication kinetics of this virus in several human epithelial cell types. The moderate virulence observed in mammalian models and the capacity for transmission in a direct contact model underscore the need for continued study of H7 subtype viruses. [ABSTRACT FROM AUTHOR]

Background: A single subtype of canine influenza virus (CIV), A(H3N8), was circulating in the United States until a new subtype, A(H3N2), was detected in Illinois in spring 2015. Since then, this CIV has caused thousands of infections in dogs in multiple states.Methods: In this study, genetic and antigenic properties of the new CIV were evaluated. In addition, structural and glycan array binding features of the recombinant hemagglutinin were determined. Replication kinetics in human airway cells and pathogenesis and transmissibility in animal models were also assessed.Results: A(H3N2) CIVs maintained molecular and antigenic features related to low pathogenicity avian influenza A(H3N2) viruses and were distinct from A(H3N8) CIVs. The structural and glycan array binding profile confirmed these findings and revealed avian-like receptor-binding specificity. While replication kinetics in human airway epithelial cells was on par with that of seasonal influenza viruses, mild-to-moderate disease was observed in infected mice and ferrets, and the virus was inefficiently transmitted among cohoused ferrets.Conclusions: Further adaptation is needed for A(H3N2) CIVs to present a likely threat to humans. However, the potential for coinfection of dogs and possible reassortment of human and other animal influenza A viruses presents an ongoing risk to public health. [ABSTRACT FROM AUTHOR]

Background: The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo.Methods: Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type.Results: We detected EBV-2 in all T-cell samples obtained from EBV-2-infected children at 12 months of age, with some children retaining EBV-2-positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva.Conclusions: These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency. [ABSTRACT FROM AUTHOR]

Background: Single low-dose primaquine (PQ) reduces Plasmodium falciparum infectivity before it impacts gametocyte density. Here, we examined the effect of PQ on gametocyte sex ratio as a possible explanation for this early sterilizing effect.Methods: Quantitative reverse-transcription polymerase chain reaction assays were developed to quantify female gametocytes (targeting Pfs25 messenger RNA [mRNA]) and male gametocytes (targeting Pf3D7_1469900 mRNA) in 2 randomized trials in Kenya and Mali, comparing dihydroartemisinin-piperaquine (DP) alone to DP with PQ. Gametocyte sex ratio was examined in relation to time since treatment and infectivity to mosquitoes.Results: In Kenya, the median proportion of male gametocytes was 0.33 at baseline. Seven days after treatment, gametocyte density was significantly reduced in the DP-PQ arm relative to the DP arm (females: 0.05% [interquartile range {IQR}, 0.0-0.7%] of baseline; males: 3.4% [IQR, 0.4%-32.9%] of baseline; P < .001). Twenty-four hours after treatment, gametocyte sex ratio became male-biased and was not significantly different between the DP and DP-PQ groups. In Mali, there was no significant difference in sex ratio between the DP and DP-PQ groups (>0.125 mg/kg) 48 hours after treatment, and gametocyte sex ratio was not associated with mosquito infection rates.Conclusions: The early sterilizing effects of PQ may not be explained by the preferential clearance of male gametocytes and may be due to an effect on gametocyte fitness. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) causes infectious mononucleosis and can lead to lymphoproliferative diseases. We evaluated the effects of valganciclovir on oral EBV shedding in a randomized, double-blind, placebo-controlled study. Twenty-six men received oral valganciclovir or daily placebo for 8 weeks, followed by a 2-week "washout period" and then 8 weeks of the alternative treatment. Valganciclovir reduced the proportion of days with EBV detected from 61.3% to 17.8% (relative risk, 0.28; 95% confidence interval [CI], .21-.41; P < .001), and quantity of virus detected by 0.77 logs (95% CI, .62-.91 logs; P < .001). Further investigations into the impact of valganciclovir on EBV-associated diseases are needed. [ABSTRACT FROM AUTHOR]

The Social Mobilization Network (SMNet) has been lauded as one of the most successsful community engagement strategies in public health for its role in polio elimination in India. The UNICEF-managed SMNet was created as a strategy to eradicate polio by engaging >7000 frontline social mobilizers to advocate for vaccination in some of the most underserved, marginalized, and at-risk communities in India. This network focused initially on generating demand for polio vaccination but later expanded its messaging to promote routine immunization and other health and sanitation interventions related to maternal and children's health. As an impact of the network's interventions, in collaboration with other eradication efforts, these high-risk pockets witnessed an increase in full routine immunization coverage. The experience of the SMNet offers lessons for health-system strengthening for social mobilization and promoting positive health behaviors for other priority health programs like the Universal Immunization Program. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus epidermidis, a major component of skin flora, is an opportunist, often causing prosthetic device infections. A family of structurally related proteins mediates staphylococcal attachment to host tissues, contributing to the success of S. epidermidis as a pathogen. We examined the ability of the surface protein SdrF to adhere to keratin, a major molecule expressed on the skin surface.Methods: A heterologous Lactococcus lactis expression system was used to express SdrF and its ligand-binding domains. Adherence to keratin types 1 and 10, human foreskin keratinocytes, and nasal epithelial cells was examined.Results: SdrF bound human keratins 1 and 10 and adhered to keratinocytes and epithelial cells. Binding involved both the A and B domains. Anti-SdrF antibodies reduced adherence of S. epidermidis to keratin and keratinocytes. RNA interference reduced keratin synthesis in keratinocytes and, as a result, SdrF adherence. Direct force measurements using atomic force microscopy showed that SdrF mediates bacterial adhesion to keratin 10 through strong and weak bonds involving the A and B regions; strong adhesion was primarily mediated by the A region.Conclusions: These studies demonstrate that SdrF mediates adherence to human keratin and suggest that SdrF may facilitate S. epidermidis colonization of the skin. [ABSTRACT FROM AUTHOR]

The term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies. [ABSTRACT FROM AUTHOR]

One of the major barriers to the successful design and implementation of human immunodeficiency virus (HIV) curative strategies is the limited ability to sensitively, specifically, and precisely quantify and characterize the whole-body burden of replication-competent HIV in individuals on effective antiretroviral therapy. Here, we review the development and validation of assays that directly and indirectly measure the size and distribution of the reservoir in blood and tissues. We also discuss the role that treatment interruptions will have in validating these assays and ultimately as a "proof of cure." [ABSTRACT FROM AUTHOR]

The latent HIV-1 reservoir in blood decays very slowly, even during prolonged suppression of viral replication by antiretroviral therapy (ART). Mechanisms for reservoir persistence include replenishment through low-level viral replication, longevity and homeostatic proliferation of memory T cells, and most recently appreciated, clonal expansion of HIV-infected cells. Clonally expanded cells make up a large and increasing fraction of the residual infected cell population on ART, and insertion of HIV proviruses into certain host cellular genes has been associated with this proliferation. That the vast majority of proviruses are defective clouds our assessment of the degree to which clonally expanded cells harbor infectious viruses, and thus the extent to which they contribute to reservoirs relevant to curing infection. This review summarizes past studies that have defined our current understanding and the gaps in our knowledge of the mechanisms by which proviral integration and clonal expansion sustain the HIV reservoir. [ABSTRACT FROM AUTHOR]

The uneven anatomic distribution of cell subsets that harbor human immunodeficiency virus (HIV) during antiretroviral therapy (ART) complicates investigation of the barriers to HIV cure. Here we propose that while previous studies done largely in blood cells have led to important investigations into HIV latency, other important mechanisms of HIV persistence during ART may not be readily apparent in the bloodstream. We specifically consider as an example the question of ongoing HIV replication during ART. We discuss how growing understanding of key anatomic sanctuaries for the virus can inform future experiments aimed at further clarifying this issue. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) type 1 uses the CD4 molecule as its principal receptor to infect T cells. HIV-1 integrates its viral genome into the host cell, leading to persistent infection wherein HIV-1 can remain transcriptionally silent in latently infected CD4+ T cells. On reactivation of replication-competent provirus, HIV-1 envelope glycoproteins (Env) are expressed and accumulate on the cell surface, allowing infected cells to be detected and targeted by endogenous immune responses or immune interventions. HIV-1 Env-specific antibodies have the potential to bind HIV-1 cell surface Env and promote elimination of infected CD4+ T cells by recruiting cytotoxic effector cells, such as natural killer cells, monocytes, and polymorphonuclear cells. Harnessing humoral and innate cellular responses has become one focus of research to develop innovative strategies to recruit and redirect cytotoxic effector cells to eliminate the HIV-1 latently infected CD4+ T-cell reservoir. [ABSTRACT FROM AUTHOR]

Background: Herpes simplex virus type 2 (HSV-2; herpes) exacerbates human immunodeficiency virus type 1 (HIV) by unclear mechanisms. These studies tested the impact of HSV-2 on systemic T-cells and HIV reservoirs.Methods: Peripheral blood mononuclear cells from HIV-infected women on antiretroviral therapy who were HSV-2 seropositive or seronegative and HIV-uninfected controls were analyzed by flow cytometry. Cell-associated HIV DNA and RNA were quantified in the absence or presence of activating stimuli, recombinant interleukin 32γ (IL-32γ), and a RUNX1 inhibitor. RNA was assessed by nanostring.Results: CD4, but not CD8, T-cell phenotypes differed in HIV+/HSV-2+ versus HIV+/HSV-2- (overall P = .002) with increased frequency of CCR5+, CXCR4+, PD-1+, and CD69+ and decreased frequency of CCR10+ and CCR6+ T-cells. The changes were associated with higher HIV DNA. Paradoxically, IL-32, a proinflammatory cytokine, was lower in subpopulations of CD4+ T-cells in HSV-2+ versus HSV-2- women. Recombinant IL-32γ blocked HIV reactivation in CD4+ T-cells and was associated with an increase in RUNX1 expression; the blockade was overcome by a RUNX1 inhibitor.Conclusions: Herpes is associated with phenotypic changes in CD4+ T-cells, including a decrease in IL-32, which may contribute to increased HIV reservoirs. Blocking IL-32 may facilitate HIV reactivation to improve shock and kill strategies. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV) is a major cause of mosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severe fatal neurologic infection. Adults aged >60 years are more susceptible to neuroinvasive disease accompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated West Nile virus vaccine, rWN/DEN4Δ30, was shown to be safe and immunogenic in healthy adults aged 18-50 years. This study evaluated rWN/DEN4Δ30 in flavivirus-naive adults aged 50-65 years and found it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safe and effective vaccine will be an important public health tool. [ABSTRACT FROM AUTHOR]

Background:  We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.Methods:  Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH).Results:  All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic.Conclusions:  SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.Clinical Trials Registration:  NCT01705990. [ABSTRACT FROM AUTHOR]

Background:  Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm.Methods:  Ninety patients with dengue during 2010-2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators.Results:  Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon γ-inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor α receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity.Conclusions:  This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is primarily spread by the Aedes aegypti and Aedes albopictus mosquito vectors. Because there is no licensed vaccine for CHIKV, identifying ways to reduce or eliminate mosquito populations is the most effective strategy to immediately halt transmission to man. Strategies to assess the entomological risk and to control the vector are absolutely crucial to demolishing the rise of CHIKV. This review provides perspectives in entomological risk assessment and vector control, challenges for both, and gaps in knowledge that need to be addressed through rigorous research and multidisciplinary collaborations. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is a reemerging alphavirus that causes acute febrile illness and severe joint pain in humans. Although acute symptoms often resolve within a few days, chronic joint and muscle pain can be long lasting. In the last decade, CHIKV has caused widespread outbreaks of unprecedented scale in the Americas, Asia, and the Indian Ocean island regions. Despite these outbreaks and the continued expansion of CHIKV into new areas, mechanisms of chikungunya pathogenesis and disease are not well understood. Experimental animal models are indispensable to the field of CHIKV research. The most commonly used experimental animal models of CHIKV infection are mice and nonhuman primates; each model has its advantages for studying different aspects of CHIKV disease. This review will provide an overview of animal models used to study CHIKV infection and disease and major advances in our understanding of chikungunya obtained from studies performed in these models. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6B (HHV-6B) commonly reactivates after umbilical cord blood transplantation (UCBT) and is associated with delayed engraftment, fever, rash, and central nervous system dysfunction. Recently, CD134 (OX40) has been implicated as a potential viral entry receptor. We evaluated CD4+CD134+/neg-lo and CD8+CD134+/neg-lo cells at day 28 after UCBT in 20 subjects with previously documented HHV-6 reactivation and persistent viremia. Analysis of CD4+CD134+ cells as compared to CD4+CD134neg-lo cells showed 0.308 versus 0.129 copies of HHV-6B/cell (P = .0002). CD8+CD134+/neg-lo cells contained little to no HHV-6B copies. Following UCBT, CD4+CD134+ cells harbor significantly increased levels of HHV-6B, suggesting that CD134 (OX40) may facilitate viral entry. [ABSTRACT FROM AUTHOR]

Limited data exist on human immunodeficiency virus type 1 (HIV-1) resistance in patients who are not responding to protease inhibitor (PI)-based regimens in resource-limited settings. This study assessed resistance profiles in adults across South Africa who were not responding to PI-based regimens. pol sequencing was undertaken and submitted to the Stanford HIV Drug Resistance Database. At least 1 major PI mutation was detected in 16.4% of 350 participants. A total of 53.4% showed intermediate resistance to darunavir/ritonavir, whereas high-level resistance was not observed. Only 5.2% and 32.8% of participants showed high-level and intermediate resistance to etravirine, respectively. Although the prevalence of major PI mutations was within previously reported ranges, most patients will likely experience virological suppression during receipt of currently available South African third-line regimens. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs, including IFN-αβ) contribute to the pathogenesis of Mycobacterium tuberculosis strains that induce high IFN-αβ levels. In the current study we examined the role of IFN-αβ during infection with a Mycobacterium africanum strain that induces low IFN-β levels. We infected wild-type and IFN-αβ receptor knockout mice with M. africanum and monitored bacterial growth, lung disease, and survival over 292 days. We found reduced lung bacterial burdens and less severe histopathological findings in the absence of IFN-αβ signaling. We conclude that IFN-αβ is pathogenic during chronic M. africanum infection and that the pathogenic effects may be mediated through poorer control of bacterial growth. [ABSTRACT FROM AUTHOR]

The current studies were undertaken to determine the susceptibility of human alveolar macrophages (AMs) to influenza A virus (IAV) infection in comparison with autologous peripheral blood-derived monocytes-macrophages (PBMs). AMs and PBMs were exposed to IAV in vitro and examined for their ability to bind and internalize IAV, and synthesize viral proteins and RNA. PBMs but not AMs demonstrated binding and internalization of the virus, synthesizing viral proteins and RNA. Exposure of AMs in the presence of a sialidase inhibitor or anti-IAV antibody resulted in viral protein synthesis by the cells. Exposure of AMs to fluorescein isothiocyanate-labeled IAV in the presence of anti-fluorescein isothiocyanate antibody also resulted in viral protein synthesis. Thus, human AMs are apparently not susceptible to direct infection by a human IAV but are likely to be infected indirectly in the setting of exposure in the presence of antibody that binds the challenging strain of IAV. [ABSTRACT FROM AUTHOR]

The mechanisms that drive the transition from commensality to invasiveness in Staphylococcus aureus are poorly understood. We recently reported that >50% of S. aureus isolates from uninfected diabetic foot ulcers in French patients harbor a prophage, ROSA-like, that is absent from invasive isolates from diabetic foot infections, including osteomyelitis. Here we show that the ROSA-like insertion abolishes the ability of S. aureus to replicate within osteoblasts, the bone-forming cells, greatly reducing damage to infected cells. These results unravel an important mechanism by which particular S. aureus strains are maintained in a commensal state in diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

For many bacterial respiratory infections, development of (severe) disease is preceded by asymptomatic colonization of the upper airways. For Streptococcus pneumoniae, the transition to severe lower respiratory tract infection is associated with an increase in nasopharyngeal colonization density. Insight into how the mucosal immune system restricts colonization may provide new strategies to prevent clinical symptoms. Several studies have provided indirect evidence that the mucosal adjuvant cholera toxin subunit B (CTB) may confer nonspecific protection against respiratory infections. Here, we show that CTB reduces the pneumococcal load in the nasopharynx, which required activation of the caspase-1/11 inflammasome, mucosal T cells, and macrophages. Our findings suggest that CTB-dependent activation of the local innate response synergizes with noncognate T cells to restrict bacterial load. Our study not only provides insight into the immunological components required for containment and clearance of pneumococcal carriage, but also highlights an important yet often understudied aspect of adjuvants. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis (VL) is a potentially fatal parasitic disease associated with fever, cachexia and impaired protective T-cell responses against the parasite.Methods: Peripheral blood leukocytes from 105 subjects with VL and healthy control subjects from the endemic region of Muzaffarpur, Bihar, India, were compared using flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. Findings were correlated with clinical data.Results: An expanded population of low-density neutrophils that expressed HLA-DR, CD80 and CD86 was observed in subjects with VL. This neutrophil population contracted after successful treatment of disease. Plasma from patients with acute VL was able to induce similar high-level HLA-DR expression in neutrophils from healthy subjects. HLA-DR+ neutrophils from subjects with VL did not stimulate T-cell proliferation, but they did express higher programmed cell death ligand-1 (PDL1) than other neutrophils, and lymphocytes of the same subjects expressed high programmed cell death 1 (PD1).Conclusions: Patients with acute VL have expanded circulating low-density neutrophils expressing markers of antigen presentation, which diminish after treatment. Development of HLA-DR+ neutrophils is stimulated, at least in part, by components of plasma from patients with acute disease. Although we found no evidence that they act as antigen-presenting cells, these neutrophils expressed markers implicating a role in T-cell exhaustion. [ABSTRACT FROM AUTHOR]

Background:  Bacterial vaginosis (BV) is characterized by low abundance of Lactobacillus species, high pH, and immune cell infiltration and has been associated with an increased risk of human papillomavirus (HPV) infection. We molecularly assessed the cervicovaginal microbiota over time in human immunodeficiency virus (HIV)-infected and HIV-uninfected women to more comprehensively study the HPV-microbiota relationship, controlling for immune status.Methods:  16S ribosomal RNA gene amplicon pyrosequencing and HPV DNA testing were conducted annually in serial cervicovaginal lavage specimens obtained over 8-10 years from African American women from Chicago, of whom 22 were HIV uninfected, 22 were HIV infected with a stable CD4+ T-cell count of > 500 cells/mm3, and 20 were HIV infected with progressive immunosuppression. Vaginal pH was serially measured.Results:  The relative abundances of Lactobacillus crispatus and other Lactobacillus species were inversely associated with vaginal pH (all P < .001). High (vs low) L. crispatus relative abundance was associated with decreased HPV detection (odds ratio, 0.48; 95% confidence interval, .24-.96; Ptrend = .03) after adjustment for repeated observation and multiple covariates, including pH and study group. However, there were no associations between HPV and the relative abundance of Lactobacillus species as a group, nor with Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii individually.Conclusions:  L. crispatus may have a beneficial effect on the burden of HPV in both HIV-infected and HIV-uninfected women (independent of pH). [ABSTRACT FROM AUTHOR]

Untreated human immunodeficiency virus (HIV) infection is characterized by progressive CD4(+) T-cell depletion and CD8(+) T-cell expansion, and CD4(+) T-cell depletion is linked directly to the risk for opportunistic infections and infection-associated mortality. With suppression of HIV replication by antiretroviral therapy, circulating CD4(+) Tcell numbers typically improve while CD8(+) T-cell expansion persists, and both CD4(+) T-cell cytopenia and CD8(+) T-cell expansion are associated with morbidity and mortality. In this brief review, we report on the role that selected homeostatic and inflammatory cytokines may play both in the failure of CD4(+) T-cell restoration and the CD8(+) T-cell expansion that characterize HIV infection. [ABSTRACT FROM AUTHOR]

Distinct pathological events occur within the gastrointestinal (GI) tract of Asian macaques with progressive simian immunodeficiency virus (SIV) infection and humans with human immunodeficiency virus type 1 (HIV-1) infection that are critical in shaping disease course. These events include depletion and functional alteration of GI-resident CD4(+) T cells, loss of antigen-presenting cells, loss of innate lymphocytes, and possible alterations to the composition of the gut microbiota. These contribute to structural damage to the GI tract and systemic translocation of GI tract microbial products. These translocated microbial products directly stimulate the immune system, and there is now overwhelming evidence that this drives chronic immune activation in HIV-1 and SIV infection. While combined antiretroviral therapy (cART) in HIV-1-infected subjects generally allows for immune reconstitution in peripheral blood, reconstitution of the GI tract occurs at a much slower pace, and both immunological and structural abnormalities persist in the GI tract. Importantly, studies of large cohorts of individuals have linked suboptimal GI reconstitution to residual inflammation and heightened morbidities in HIV-1-infected cART recipients. As a result, current era treatments aimed at augmenting restoration of the GI tract hold promise in returning cART recipients to full health. [ABSTRACT FROM AUTHOR]

Streptococcus oralis forms robust mucosal biofilms with Candida albicans that have increased pathogenic potential. In this study, using oral epithelial cultures, organotypic oral mucosal constructs, and a mouse model of oral infection, we demonstrated that S. oralis augmented C. albicans invasion through epithelial junctions. C. albicans and S. oralis decreased epithelial E-cadherin levels by synergistically increasing µ-calpain, a proteolytic enzyme that targets E-cadherin. In the mouse coinfection model this was accompanied by increased fungal kidney dissemination. Coinfection with a secreted aspartyl protease (sap) mutant sap2456 and S. oralis increased μ-calpain and triggered mucosal invasion and systemic dissemination, suggesting that fungal protease activity is not required for invasion during coinfection. We conclude that C. albicans and S. oralis synergize to activate host enzymes that cleave epithelial junction proteins and increase fungal invasion. [ABSTRACT FROM AUTHOR]

Pellino 1 positively regulates Toll-like receptor 4 signaling by regulating tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and is suppressed with the induction of endotoxin tolerance. However, the role of TRAF3 in endotoxin tolerance is largely unknown. In this study, we found that lipopolysaccharide (LPS) stimulation decreased TARF3 protein expression in mouse Kupffer cells (KCs) and liver tissues, whereas endotoxin tolerization abrogated this effect. Degradative TRAF3 K48-linked ubiquitination and the cytoplasmic translocation of the MYD88-associated multiprotein complex were significantly inhibited in tolerized KCs, which led to markedly impaired activation of MYD88-dependent JNK and p38 and downregulation of inflammatory cytokines. TRAF3 ablation failed to induce a fully endotoxin-tolerant state in RAW264.7 cells. Pellino 1 knockdown in Raw264.7 cells did not impair induction of cIAP2 in response to LPS but inhibited the K63-linked ubiquitination of cellular inhibitor of apoptosis protein 2 (cIAP2) and K48-linked ubiquitination of TRAF3 protein. We also found upregulation of Pellino 1 and downregulation of TRAF3 in liver tissues of patients with cholangitis. Our findings reveal a novel mechanism that endotoxin tolerance reprograms mitogen-activated protein kinase signaling by suppressing Pellino 1-mediated K63-linked ubiquitination of cIAP2, K48-linked ubiquitination, and degradation of TRAF3. [ABSTRACT FROM AUTHOR]

Macrophages can polarize and differentiate to regulate initiation, development, and cessation of inflammation during pulmonary infection with nontypeable Haemophilus influenzae (NTHi). However, the underlying molecular mechanisms driving macrophage phenotypic differentiation are largely unclear. Our study investigated the role of Shp2, a Src homology 2 domain-containing phosphatase, in the regulation of pulmonary inflammation and bacterial clearance. Shp2 levels were increased upon NTHi stimulation. Selective inhibition of Shp2 in mice led to an attenuated inflammatory response by skewing macrophages toward alternatively activated macrophage (M2) polarization. Upon pulmonary NTHi infection, Shp2(-/-) mice, in which the gene encoding Shp2 in monocytes/macrophages was deleted, showed an impaired inflammatory response and decreased antibacterial ability, compared with wild-type controls. In vitro data demonstrated that Shp2 regulated activated macrophage (M1) gene expression via activation of p65-nuclear factor-κB signaling, independent of p38 and extracellular regulated kinase-mitogen-activated proteins kinase signaling pathways. Taken together, our study indicates that Shp2 is required to orchestrate macrophage function and regulate host innate immunity against pulmonary bacterial infection. [ABSTRACT FROM AUTHOR]

Bacterial vaginosis (BV) affects almost a quarter of US women, making it a condition of major public health relevance. Key questions remain regarding the etiology of BV, mechanisms for its association with poor reproductive health outcomes, and reasons for high rates of treatment failure. New model systems are required to answer these remaining questions, elucidate the complex host-microbe and microbe-microbe interactions, and develop new, effective interventions. In this review, we cover the strengths and limitations of in vitro and in vivo model systems to study these complex intercellular interactions. Furthermore, we discuss advancements needed to maximize the translational utility of the model systems. As no single model can recapitulate all of the complex physiological and environmental conditions of the human vaginal microenvironment, we conclude that combinatorial approaches using in vitro and in vivo model systems will be required to address the remaining fundamental questions surrounding the enigma that is BV. [ABSTRACT FROM AUTHOR]

Practitioners and patients alike widely recognize the limitations of current therapeutic approaches to the treatment of bacterial vaginosis (BV). Options remain extremely limited, and our inability to prevent the frequently, often relentless symptomatic recurrences of BV and to reduce serious sequelae such as preterm delivery, remains an acknowledged but unresolved shortcoming. Our incomplete understanding of the pathophysiology of this unique form of vaginal dysbiosis has been a significant impediment to developing optimal treatment and prevention approaches. New drugs have not been forthcoming and are not likely to be available in the immediate future; hence, reliance on the optimal use of available agents has become essential as improvised often unproven regimens are implemented. In this review, we will explore the limitations of currently recommended therapies, with a particular focus on the contribution of reinfection and pathogen persistence to BV recurrence, and the development of interventions that target these mechanisms. Ultimately, to achieve sustained cure and effectiveness against BV-associated sequelae, it is possible that we will need approaches that combine antimicrobials with biofilm-disrupting agents and partner treatments in those at risk of reinfection. [ABSTRACT FROM AUTHOR]

Helminth-infected individuals possess a higher risk of developing tuberculosis, but the precise immunologic mechanism of Mycobacterium tuberculosis control remains unclear. We hypothesized that a perturbation of the M. tuberculosis-specific CD4(+) T-cell response weakens the ability of macrophages to contain M. tuberculosis We exposed peripheral blood mononuclear cells from M. tuberculosis-infected humans to schistosome soluble egg antigen (SEA) and then profiled M. tuberculosis-specific CD4(+) T cells via multiparametric flow cytometry. SEA decreased the frequency of cells producing interferon γ (6.79% vs 3.20%; P = .017) and tumor necrosis factor α (6.98% vs 2.96%; P = .012), with a concomitant increase in the median fluorescence intensity of interleukin 4 (IL-4; P < .05) and interleukin 10 (IL-10; 1440 vs 1273; P < .05). Macrophages polarized with SEA-exposed, autologous CD4(+) T-cell supernatant had a 2.19-fold decreased colocalization of lysosomes and M. tuberculosis (P < .05). When polarized with IL-4 or IL-10, macrophages had increased expression of CD206 (P < .0001), 1.5-fold and 1.9 fold increased intracellular numbers of M. tuberculosis per macrophage (P < .0005), and 1.4-fold and 1.7-fold decreased colocalization between M. tuberculosis and lysosomes (P < .001). This clarifies a relationship in which helminth-induced CD4(+) T cells disrupt M. tuberculosis control by macrophages, thereby providing a mechanism for the observation that helminth infection advances the progression of tuberculosis among patients with M. tuberculosis infection. [ABSTRACT FROM AUTHOR]