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Introduction: With low COVID-19 vaccination coverage, non-pharmaceutical interventions were critical to mitigating the COVID-19 pandemic in Sudan. We explored changes in social contact patterns, risk perception, attitudes, and practices toward protective measures during an evolving COVID-19 outbreak in six illustrative communities in Sudan., Methods: This qualitative study took place in six communities in five Sudanese states using focus group discussions with community members and non-participant structured observations in public spaces between March 2021 and April 2021. A total of 117 participants joined 24 group discussions. We used a two-stage thematic analysis., Results: The perceived importance of compliance with individual preventative measures among those who believe in COVID-19 was higher than observed compliance with behaviors in most study sites. Adherence was consistently low and mainly driven by enforced movement restrictions. As restrictions were lifted, social contacts outside the household resumed pre-COVID-19 levels, and risk perception and individual and institutional adherence to protective measures diminished. We identified an environment that is socially and economically unsupportive of preventive practices, compounded by widespread rumours, misinformation, and mistrust in the government-led response. However, we identified new social habits that can contribute to reducing COVID-19 transmission., Conclusion: The unfavourable social and economic environment, coupled with the low visibility of the pandemic and pandemic response, has likely modulated the influence of higher risk perception on adopting precautionary behaviours by individuals. Governments and non-governmental actors should increase the visibility of the pandemic and pandemic response, enforce and incentivise infection control measures in public areas, promote emerging preventive social habits, and actively track and address rumours and misinformation related to COVID-19 and COVID-19 vaccines., (© 2024. The Author(s).)

Background: Population mortality is an important metric that sums information from different public health risk factors into a single indicator of health. However, the impact of COVID-19 on population mortality in low-income and crisis-affected countries like Sudan remains difficult to measure. Using a community-led approach, we estimated excess mortality during the COVID-19 epidemic in two Sudanese communities., Methods: Three sets of key informants in two study locations, identified by community-based research teams, were administered a standardised questionnaire to list all known decedents from January 2017 to February 2021. Based on key variables, we linked the records before analysing the data using a capture-recapture statistical technique that models the overlap among lists to estimate the true number of deaths., Results: We estimated that deaths per day were 5.5 times higher between March 2020 and February 2021 compared to the pre-pandemic period in East Gezira, while in El Obeid City, the rate was 1.6 times higher., Conclusion: This study suggests that using a community-led capture-recapture methodology to measure excess mortality is a feasible approach in Sudan and similar settings. Deploying similar community-led estimation methodologies should be considered wherever crises and weak health infrastructure prevent an accurate and timely real-time understanding of epidemics' mortality impact in real-time., (© 2024. The Author(s).)

Somalia is one of 20 countries in the world with the highest numbers of zero-dose children. This study aims to identify who and where zero-dose and under-vaccinated children are and what the existing vaccine delivery strategies to reach zero-dose children in Somalia are. This qualitative study was conducted in three geographically diverse regions of Somalia (rural/remote, nomadic/pastoralists, IDPs, and urban poor population), with government officials and NGO staff ( n = 17), and with vaccinators and community members ( n = 52). The data were analyzed using the GAVI Vaccine Alliance IRMMA framework. Nomadic populations, internally displaced persons, and populations living in remote and Al-shabaab-controlled areas are three vulnerable and neglected populations with a high proportion of zero-dose children. Despite the contextual heterogeneity of these population groups, the lack of targeted, population-specific strategies and meaningful engagement of local communities in the planning and implementation of immunization services is problematic in effectively reaching zero-dose children. This is, to our knowledge, the first study that examines vaccination strategies for zero-dose and under-vaccinated populations in the fragile context of Somalia. Evidence on populations at risk of vaccine-preventable diseases and barriers to vital vaccination services remain critical and urgent, especially in a country like Somalia with complex health system challenges.

The persistence of inadequate vaccination in crisis-affected settings raises concerns about decision making regarding vaccine selection, timing, location, and recipients. This review aims to describe the key features of childhood vaccination intervention design and planning in crisis-affected settings and investigate how the governance of childhood vaccination is defined, understood, and practised. We performed a scoping review of 193 peer-reviewed articles and grey literature on vaccination governance and service design and planning. We focused on 41 crises between 2010 and 2021. Following screening and data extraction, our analysis involved descriptive statistics and applying the governance analysis framework to code text excerpts, employing deductive and inductive approaches. Most documents related to active outbreaks in conflict-affected settings and to the mass delivery of polio, cholera, and measles vaccines. Information on vaccination modalities, target populations, vaccine sources, and funding was limited. We found various interpretations of governance, often implying hierarchical authority and regulation. Analysis of governance arrangements suggests a multi-actor yet fragmented governance structure, with inequitable actor participation, ineffective actor collaboration, and a lack of a shared strategic vision due to competing priorities and accountabilities. Better documentation of vaccination efforts during emergencies, including vaccination decision making, governance, and planning, is needed. We recommend empirical research within decision-making spaces.

Objectives: During the COVID-19 pandemic, most essential services experienced some level of disruption. Disruption in LMICs was more severe than in HICs. Early reports suggested that services for maternal and newborn health were disproportionately affected, raising concerns about health equity. Most disruption indicators measure demand-side disruption, or they conflate demand-side and supply-side disruption. There is currently no published guidance on measuring supply-side disruption. The primary objective of this review was to identify methods and approaches used to measure supply-side service disruptions to maternal and newborn health services in the context of COVID-19., Design: We carried out a systematic review and have created a typology of measurement methods and approaches using narrative synthesis., Data Sources: We searched MEDLINE, EMBASE and Global Health in January 2023. We also searched the grey literature., Eligibility Criteria: We included empirical studies describing the measurement of supply-side service disruption of maternal and newborn health services in LMICs in the context of COVID-19., Data Extraction and Synthesis: We extracted the aim, method(s), setting, and study outcome(s) from included studies. We synthesised findings by type of measure (ie, provision or quality of services) and methodological approach (ie, qualitative or quantitative)., Results: We identified 28 studies describing 5 approaches to measuring supply-side disruption: (1) cross-sectional surveys of the nature and experience of supply-side disruption, (2) surveys to measure temporal changes in service provision or quality, (3) surveys to create composite disruption scores, (4) surveys of service users to measure receipt of services, and (5) clinical observation of the provision and quality of services., Conclusion: Our review identified methods and approaches for measuring supply-side service disruption of maternal and newborn health services. These indicators provide important information about the causes and extent of supply-side disruption and provide a useful starting point for developing specific guidance on the measurement of service disruption in LMICs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Delivering vaccines in humanitarian response requires rigourous and continuous analysis of evidence. This systematic review mapped the normative landscape of vaccination guidance on vaccine-preventable diseases in crisis-affected settings. Guidance published between 2000 and 2022 was searched for, in English and French, on websites of humanitarian actors, Google, and Bing. Peer-reviewed database searches were performed in Global Health and Embase. Reference lists of all included documents were screened. We disseminated an online survey to professionals working in vaccination delivery in humanitarian contexts. There was a total of 48 eligible guidance documents, including technical guidance ( n = 17), descriptive guidance ( n = 16), operational guidance ( n = 11), evidence reviews ( n = 3), and ethical guidance ( n = 1). Most were World Health Organization documents ( n = 21) targeting children under 5 years of age. Critical appraisal revealed insufficient inclusion of affected populations and limited rigour in guideline development. We found limited information on vaccines including, yellow fever, cholera, meningococcal, hepatitis A, and varicella, as well as human papilloma virus (HPV). There is a plethora of vaccination guidance for vaccine-preventable diseases in humanitarian contexts. However, gaps remain in the critical and systematic inclusion of evidence, inclusion of the concept of "zero-dose" children and affected populations, ethical guidance, and specific recommendations for HPV and non-universally recommended vaccines, which must be addressed.

Not all COVID-19 deaths are officially reported, and particularly in low-income and humanitarian settings, the magnitude of reporting gaps remains sparsely characterized. Alternative data sources, including burial site worker reports, satellite imagery of cemeteries, and social media-conducted surveys of infection may offer solutions. By merging these data with independently conducted, representative serological studies within a mathematical modeling framework, we aim to better understand the range of underreporting using examples from three major cities: Addis Ababa (Ethiopia), Aden (Yemen), and Khartoum (Sudan) during 2020. We estimate that 69 to 100%, 0.8 to 8.0%, and 3.0 to 6.0% of COVID-19 deaths were reported in each setting, respectively. In future epidemics, and in settings where vital registration systems are limited, using multiple alternative data sources could provide critically needed, improved estimates of epidemic impact. However, ultimately, these systems are needed to ensure that, in contrast to COVID-19, the impact of future pandemics or other drivers of mortality is reported and understood worldwide.

The estimation of population denominators of internally displaced people (IDP) and other crisis-affected populations is a foundational step that facilitates all humanitarian assistance. However, the humanitarian system remains somewhat tolerant of irregular and inaccurate estimates of population size and composition, particularly of IDPs. In this commentary, we review how humanitarian organizations currently approach the estimation of IDP populations, and how field approaches and analytical methodologies can be improved and integrated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Ltd.)

Background: Risk communication interventions during epidemics aim to modify risk perceptions to achieve rapid shifts in population health behaviours. Exposure to frequent and often concurrent epidemics may influence how the public and health professionals perceive and respond to epidemic risks. This review aimed to systematically examine the evidence on risk perceptions of epidemic-prone diseases in countries highly vulnerable to epidemics., Methods: We conducted a systematic review using PRISMA standards. We included peer-reviewed studies describing or measuring risk perceptions of epidemic-prone diseases among the general adult population or health professionals in 62 countries considered highly vulnerable to epidemics. We searched seven bibliographic databases and applied a four-stage screening and selection process, followed by quality appraisal. We conducted a narrative meta-synthesis and descriptive summary of the evidence, guided by the Social Amplification of Risk Framework., Results: Fifty-six studies were eligible for the final review. They were conducted in eighteen countries and addressed thirteen epidemic-prone diseases. Forty-five studies were quantitative, six qualitative and five used mixed methods. Forty-one studies described epidemic risk perceptions in the general public and nineteen among health professionals. Perceived severity of epidemic-prone diseases appeared high across public and health professional populations. However, perceived likelihood of acquiring disease varied from low to moderate to high among the general public, and appeared consistently high amongst health professionals. Other occupational groups with high exposure to specific diseases, such as bushmeat handlers, reported even lower perceived likelihood than the general population. Among health professionals, the safety and effectiveness of the work environment and of the broader health system response influenced perceptions. Among the general population, disease severity, familiarity and controllability of diseases were influential factors. However, the evidence on how epidemic risk perceptions are formed or modified in these populations is limited., Conclusions: The evidence affords some insights into patterns of epidemic risk perception and influencing factors, but inadequately explores what underlies perceptions and their variability, particularly among diseases, populations and over time. Approaches to defining and measuring epidemic risk perceptions are relatively underdeveloped., (© 2022. The Author(s).)

Background: Shielding of high-risk groups from coronavirus disease (COVID-19) has been suggested as a realistic alternative to severe movement restrictions during the COVID-19 epidemic in low-income countries. The intervention entails the establishment of 'green zones' for high-risk persons to live in, either within their homes or in communal structures, in a safe and dignified manner, for extended periods of time during the epidemic. To our knowledge, this concept has not been tested or evaluated in resource-poor settings. This study aimed to explore the acceptability and feasibility of strategies to shield persons at higher risk of severe COVID-19 outcomes, during the COVID-19 epidemic in six communities in Sudan., Methods: We purposively sampled participants from six communities, illustrative of urban, rural and forcibly-displaced settings. In-depth telephone interviews were held with 59 members of households with one or more members at higher risk of severe COVID-19 outcomes. Follow-up interviews were held with 30 community members after movement restrictions were eased across the country. All interviews were audio-recorded, transcribed verbatim, and analysed using a two-stage deductive and inductive thematic analysis., Results: Most participants were aware that some people are at higher risk of severe COVID-19 outcomes but were unaware of the concept of shielding. Most participants found shielding acceptable and consistent with cultural inclinations to respect elders and protect the vulnerable. However, extra-household shielding arrangements were mostly seen as socially unacceptable. Participants reported feasibility concerns related to the reduced socialisation of shielded persons and loss of income for shielding families. The acceptability and feasibility of shielding strategies were reduced after movement restrictions were eased, as participants reported lower perception of risk in their communities and increased pressure to comply with social commitments outside the house., Conclusion: Shielding is generally acceptable in the study communities. Acceptability is influenced by feasibility, and by contextual changes in the epidemic and associated policy response. The promotion of shielding should capitalise on the cultural and moral sense of duty towards elders and vulnerable groups. Communities and households should be provided with practical guidance to implement feasible shielding options. Households must be socially, psychologically and financially supported to adopt and sustain shielding effectively.

Background: Large international humanitarian actors support and directly deliver health services for millions of people in crises annually, and wield considerable power to decide which health services to provide, how and to whom, across a vast spectrum of health areas. Despite decades of reform aiming to improve accountability in the sector, public health practice among humanitarian actors is not heavily scrutinized in either the countries where they are headquartered or those where they provide healthcare. We surveyed current healthcare governance practice among large international humanitarian actors to better understand what organisations are doing to ensure oversight and accountability for health services in humanitarian responses., Methods: The term 'healthcare governance' was defined and categorised into seven domains: implementation of health management information systems (HMIS) and use of resulting data; professional development of health sector staff; audits of health service performance; management of clinical incidents; evidence-based practice; pharmaceutical supply; and beneficiary engagement. Senior health professionals at 32 leading international actors providing humanitarian health services were contacted between July and August 2019 to complete a 109-question online survey about their organisation's practice in these domains., Results: Respondents from 13 organisations completed the questionnaire. Healthcare governance practices were undertaken to varying degrees by all organisations but were often driven by donor requirements and external factors rather than improvement of programme performance. Common strengths were the inclusion of governance in organisational policies, high availability of technical guidelines, and close monitoring of pharmaceutical services. Recurring weaknesses were poor beneficiary engagement, inconsistent use of health information for decision making, unsystematic implementation of healthcare audits, inconsistent management of clinical incidents, and lack of training and professional development opportunities., Conclusions: To our knowledge, this is the first study to describe healthcare governance practice among humanitarian actors. Leading international humanitarian healthcare providers are already implementing many healthcare governance activities; however, these are inconsistently applied and generally not reflective of systematic policies or earmarked organisational resources. There is a need for sector-wide consensus on how the humanitarian sector defines healthcare governance, the domains that constitute it, which actors in the humanitarian system are implicated, and how malpractice should be systematically addressed.

The COVID-19 pandemic has the potential to cause high morbidity and mortality in crisis-affected populations. Delivering COVID-19 treatment services in crisis settings will likely entail complex trade-offs between offering services of clinical benefit and minimising risks of nosocomial infection, while allocating resources appropriately and safeguarding other essential services. This paper outlines considerations for humanitarian actors planning COVID-19 treatment services where vaccination is not yet widely available. We suggest key decision-making considerations: allocation of resources to COVID-19 treatment services and the design of clinical services should be based on community preferences, likely opportunity costs, and a clearly articulated package of care across different health system levels. Moreover, appropriate service planning requires information on the expected COVID-19 burden and the resilience of the health system. We explore COVID-19 treatment service options at the patient level (diagnosis, management, location and level of treatment) and measures to reduce nosocomial transmission (cohorting patients, protecting healthcare workers). Lastly, we propose key indicators for monitoring COVID-19 health services., Competing Interests: Competing interestsThe authors do not report any competing interests., (© The Author(s) 2020.)

Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22-mediated inhibition of T cell-derived IFN-γ expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Since December 2018, the latest wave of anti-government protests in Sudan has led to deaths, injuries and detentions. We estimated the number of people killed and described patterns of deaths, injuries and detentions up to 9 April 2019., Methods: We tabulated data from three publicly available lists maintained by Sudanese civil society sources (the Independent Movement, the Sudan Doctors' Union and the "Lest We Forget" project), and applied to these a capture-recapture statistical technique that models the overlap among lists to estimate the number of deaths not on any list., Results: We estimated that about 117 civilians were killed in demonstrations during the above period, a considerably larger number than hitherto reported. Most decedents and injury victims were shot., Conclusions: This analysis demonstrates the importance of real-time data on political violence collected by civil society initiatives. The de facto Sudanese government should immediately cease attacks against peaceful civilian protesters and put in place guarantees for their safety., Competing Interests: The study relied exclusively on data available in the public domain and was approved by the London School of Hygiene and Tropical Medicine Ethics Committee.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Elevated antibody levels against Epstein-Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology., Objectives: To examine effects of high-dose oral vitamin D 3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS., Methods: Serum 25-hydroxyvitamin D 3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385-420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D 3 supplementation (20,000 IU/week) (NCT00785473)., Results: The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 ( p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D 3 supplementation did not affect antibodies against VCA, CMV or VZV., Conclusion: The results indicate that high-dose oral vitamin D 3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.

Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

Dendritic cells are professional APCs that play a central role in the initiation of immune responses. The limited ex vivo availability of dendritic cells inspires the widespread use of bone marrow-derived dendritic cells as an alternative in research. However, the functional characteristics of bone marrow-derived dendritic cells are incompletely understood. Therefore, we compared functional and phenotypic characteristics of rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3 ligand bone marrow-derived dendritic cells. A comparison of surface markers revealed that FLT3 ligand-bone marrow-derived dendritic cells expressed signal regulatory protein α, CD103, and CD4 and baseline levels of MHC class II, CD40, and CD86, which were highly up-regulated upon stimulation. Conversely, GM-CSF/IL-4-bone marrow-derived dendritic cells constitutively expressed signal regulatory protein α, CD11c, and CD11b but only mildly up-regulated MHC class II, CD40, or CD86 following stimulation. Expression of dendritic cell-associated core transcripts was restricted to FLT3 ligand-bone marrow-derived dendritic cells . GM-CSF/IL-4-bone marrow-derived dendritic cells were superior at phagocytosis but were outperformed by FLT3 ligand-bone marrow-derived dendritic cells at antigen presentation and T cell stimulation in vitro. Stimulated GM-CSF/IL-4-bone marrow-derived dendritic cells secreted more TNF, CCL5, CCL20, and NO, whereas FLT3 ligand-bone marrow-derived dendritic cells secreted more IL-6 and IL-12. Finally, whereas GM-CSF/IL-4-bone marrow-derived dendritic cell culture supernatants added to resting T cell cultures promoted forkhead box p3(+) regulatory T cell populations, FLT3 ligand-bone marrow-derived dendritic cell culture supernatants drove Th17 differentiation. We conclude that rat GM-CSF/IL-4-bone marrow-derived dendritic cells and FLT3 ligand-bone marrow-derived dendritic cells are functionally distinct. Our data support the current rationale that FLT3 ligand-bone marrow-derived dendritic cells mostly resemble classic dendritic cells but comprise additional minor subpopulations, whereas GM-CSF/IL-4-bone marrow-derived dendritic cells resemble monocyte-derived inflammatory dendritic cells (iNOS-positive monocyte-derived cells)., (© Society for Leukocyte Biology.)

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking., Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2 (-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures., Results: Expression of Cr2 in naïve spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA., Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.

Herpes simplex encephalitis (HSE) is a rare disease with high mortality and significant morbidity among survivors. We have previously shown that susceptibility to HSE was host-strain dependent, as severe, lethal HSE developed after injection of human Herpes simplex type 1 virus (HSV-1) into the whiskers area of DA rats, whereas PVG rats remained completely asymptomatic. In the present study we investigated the early immunokinetics in these strains to address the underlying molecular mechanisms for the observed difference. The virus distribution and the immunological responses were compared in the whiskers area, trigeminal ganglia and brain stem after 12 hours and the first four days following infection using immunohistochemistry and qRT-PCR. A conspicuous immunopathological finding was a strain-dependent difference in the spread of the HSV-1 virus to the trigeminal ganglia, only seen in DA rats already from 12 hpi. In the whiskers area infected perineurial cells were abundant in the susceptible DA strain after 2 dpi, whereas in the resistant PVG rats HSV-1 spread was confined only to the epineurium. In both strains activation of Iba1(+)/ED1(+) phagocytic cells followed the distribution pattern of HSV-1 staining, which was visible already at 12 hours after infection. Notably, in PVG rats higher mRNA expression of Toll-like receptors (Tlr) -2 and -9, together with increased staining for Iba1/ED1 was detected in the whiskers area. In contrast, all other Tlr-pathway markers were expressed at higher levels in the susceptible DA rats. Our data demonstrate the novel observation that genetically encoded properties of the host nerve and perineurial cells, recruitment of phagocyting cells together with the low expression of Tlr2 and -9 in the periphery define the susceptibility to HSV-1 entry into the nervous system.

Local CNS inflammation takes place in many neurological disorders and is important for autoimmune neuroinflammation. Microglial activation is strain-dependent in rats and differential MHC class II expression is influenced by variations in the Mhc2ta gene. Despite sharing Mhc2ta and MHC class II alleles, BN and LEW.1N rats differ in MHC class II expression after ventral root avulsion (VRA). We studied MHC class II expression and glial activation markers in BN rats after VRA. Our results demonstrate that MHC class II expression originates from a subpopulation of IBA1(+), ED1(-), and ED2(-) microglia. We subsequently performed a genome-wide linkage scan in an F2(BNxLEW.1N) population, to investigate gene regions regulating this inflammatory response. Alongside MHC class II, we studied the expression of MHC class I, co-stimulatory molecules, complement components, microglial markers and Il1b. MHC class II and other transcripts were commonly regulated by gene regions on chromosomes 1 and 7. Furthermore, a common region on chromosome 10 regulated expression of complement and co-stimulatory molecules, while a region on chromosome 11 regulated MHC class I. We also detected epistatic interactions in the regulation of the inflammatory process. These results reveal the complex regulation of CNS inflammation by several gene regions, which may have relevance for disease.