Host Age Research Articles

Exposure of small ruminants to the Schmallenberg arbovirus in Germany from 2017 to 2018 – animal-specific and flock-management-related risk factors

The Schmallenberg virus (SBV), an emerging Orthobunyavirus of mainly ruminant hosts, caused a substantial epidemic in European ruminant populations between 2011 and 2013. The pathogen is transmitted by arthropod vectors (Culicoides spp.) and can cause reproductive disorders and severe malformations of the offspring or stillbirth. The present study aimed to assess SBV seroprevalence among German sheep and goats a few years after the first virus detection in the country (November 2011). In addition, an extensive risk factor analysis including host-specific and husbandry-related factors was implemented. Seroprevalence was determined by examining serum samples from 2759 sheep and 446 goats out of a total of 70 flocks across five German federal states. The samples were withdrawn in the period between 2017 and 2018. Using a commercial competitive ELISA, antibodies against SBV were detected in all 70 investigated flocks. A percentage of 60.1 % (1657/2759) of the sheep and 40.4 % (180/446) of the goat sera contained SBV antibodies. Generalized linear mixed modeling revealed significant effects of host species (sheep > goats), age (old > young) and sex (female > male) on SBV seroprevalence. For both species, also the farming purpose, and for goats, ectoparasite treatment and the presence of cattle on the farm played a role in terms of risk for SBV exposure. The observations from this study still emphasize a wide distribution of the pathogen in Germany. Nevertheless, the observed seroprevalence might not be sufficient to achieve effective herd immunity. Pinpointing risk factors identified susceptible populations for targeted vaccination programs to reduce potential animal losses caused by SBV.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue ‘counting’ beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

IGATE analysis improves the interpretability of single-cell immune landscape of influenza infection.

Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host factors such as genetic background and aging affect the single-cell immune landscape of influenza infection. Cytometry by time-of-flight (CyTOF) represents a promising technique in this pursuit, but interpreting its large, high-dimensional data remains difficult. We have developed a new analytical approach, in silico gating annotating training elucidating (iGATE), based on probabilistic support vector machine classification. By rapidly and accurately "gating" tens of millions of cells in silico into user-defined types, iGATE enabled us to track 25 canonical immune cell types in mouse lung over the course of influenza infection. Applying iGATE to study effects of host genetic background, we show that the lower survival of C57BL/6 mice compared with BALB/c was associated with a more rapid accumulation of inflammatory cell types and decreased IL-10 expression. Furthermore, we demonstrate that the most prominent effect of aging is a defective T cell response, reducing survival of aged mice. Finally, iGATE reveals that the 25 canonical immune cell types exhibited differential influenza infection susceptibility and replication permissiveness in vivo, but neither property varied with host genotype or aging. The software is available at https://github.com/UmichWenLab/iGATE.

Ecto- and endoparasites of common reedbuck, Redunca arundinum, at 2 localities in KwaZulu-Natal Province, South Africa: community and network structure.

Parasite community structure is governed by functional traits of hosts and parasites. Notably, parasite populations and communities respond to host social and spatial behaviour. Many studies demonstrating these effects dealt with small-bodied host species, while the influence of host social patterns on parasite communities in large hosts remains understudied. In an earlier study on nyalas (Tragelaphus angasii), host age was more important than sex in structuring helminth communities and networks, but the influence of both was mediated by local environmental conditions, creating different locality patterns. Common reedbuck (Redunca arundinum) differ from nyalas in spatial and social behaviour. Based on helminth and ectoparasite data from 56 reedbuck examined at 2 localities in KwaZulu-Natal Province, we asked which patterns are similar and which differ between the 2 host species. Similar to nyalas, reedbuck age was more important than sex in structuring communities and networks. However, local environmental conditions exerted the strongest influence on transmission patterns, especially in ectoparasites. Complex interactions between reedbuck traits, parasite traits and local environmental conditions modulated the risk of infection differently at the 2 sites, confirming our earlier findings in nyalas that pooling data from different locations may obscure location-specific parasite community patterns. Similarities between patterns in reedbuck and nyalas, despite their behavioural differences, suggest some common patterns in parasite community ecology that, in turn, are determined mostly by parasite traits and population dynamics.

Development of die drawing design factor prediction models for trenchless rehabilitation of water pipes: a case study

ABSTRACT Maintenance and replacement of aging water pipes are critical for urban development. To this end, trenchless rehabilitation methods that do not require excavation offer an efficient replacement for aging water pipes. Thus, this study developed a trenchless method using die drawing, which continuously inserts polyethylene (PE) liners into the reach point while maintaining traction in the host aging pipe. If the traction is removed after a certain period, the initially contracted liner pipe undergoes expansion under natural restoration and tightly adheres to the inner wall of the host pipe to achieve structural regeneration of the aging pipe. This study aimed to determine the factors influencing the die drawing process using a rehabilitation design. Accordingly, we experimented with the die drawing method to achieve structural reinforcement using high elasticity PE liners. Thereafter, based on the experimental data, we developed prediction models to estimate traction, pipe restoration rate after traction release, and pipe restoration period. The developed models estimated the minimum required restoration period and provided deeper insights into the restoration behavior of the die drawing method employed in pre-equipment maintenance before on-site construction.

Bacteria-organelle communication in physiology and disease.

Bacteria, omnipresent in our environment and coexisting within our body, exert dual beneficial and pathogenic influences. These microorganisms engage in intricate interactions with the human body, impacting both human health and disease. Simultaneously, certain organelles within our cells share an evolutionary relationship with bacteria, particularly mitochondria, best known for their energy production role and their dynamic interaction with each other and other organelles. In recent years, communication between bacteria and mitochondria has emerged as a new mechanism for regulating the host's physiology and pathology. In this review, we delve into the dynamic communications between bacteria and host mitochondria, shedding light on their collaborative regulation of host immune response, metabolism, aging, and longevity. Additionally, we discuss bacterial interactions with other organelles, including chloroplasts, lysosomes, and the endoplasmic reticulum (ER).

Virological, innate, and adaptive immune profiles shaped by variation in route and age of host in murine cytomegalovirus infection.

The majority of experiments modeling human cytomegalovirus (hCMV) infection in mice have been carried out using intraperitoneal infection in sexually mature adult mice, which stands in contrast to the large number of humans being infected with human CMV at a young age, most likely via bodily fluids through the nasopharyngeal/oral route. This study examined the impact of the choice of age and route of infection in modeling CMV infection in mice. By comparing young, prepubescent to older sexually mature counterparts, infected either via the intranasal or intraperitoneal route, we discovered substantial differences in deployment and response intensity of different arms of the immune system in systemic control of the virus; tissue responses, by contrast, appeared similar between ages and infection routes.

Modeling the transmission dynamics of a two-strain dengue disease with infection age

In this paper, we introduce a partial differential equation (PDE) model to describe the transmission dynamics of dengue with two viral strains and possible secondary infection for humans. The model features the variable infectiousness during the infectious period, which we call the infection age of the infectious host. We define two thresholds [Formula: see text] and [Formula: see text], and show that the strain [Formula: see text] can not invade the system if [Formula: see text]. Further, the disease-free equilibrium of the system is globally asymptotically stable if [Formula: see text]. When [Formula: see text], strain [Formula: see text] dominance equilibrium [Formula: see text] exists, and is locally asymptotically stable when [Formula: see text], [Formula: see text], [Formula: see text]. Then, by applying Lyapunov–LaSalle techniques, we establish the global asymptotical stability of the dominance equilibrium corresponding to some strain [Formula: see text]. This implies strain [Formula: see text] eliminates the other strain as long as [Formula: see text], where [Formula: see text] denotes the probability of a given susceptible mosquito being transmitted by a primarily infected human with strain [Formula: see text]. Finally, we study the existence of the coexistence equilibria under some conditions.

The impacts of host association and perturbation on symbiont fitness

Symbiosis can benefit hosts in numerous ways, but less is known about whether interactions with hosts benefit symbionts—the smaller species in the relationship. To determine the fitness impact of host association on symbionts in likely mutualisms, we conducted a meta-analysis across 91 unique host-symbiont pairings under a range of spatial and temporal contexts. Specifically, we assess the consequences to symbiont fitness when in and out of symbiosis, as well as when the symbiosis is under suboptimal or varying environments and biological conditions (e.g., host age). We find that some intracellular symbionts associated with protists tend to have greater fitness when the symbiosis is under stressful conditions. Symbionts of plants and animals did not exhibit this trend, suggesting that symbionts of multicellular hosts are more robust to perturbations. Symbiont fitness also generally increased with host age. Lastly, we show that symbionts able to proliferate in- and outside host cells exhibit greater fitness than those found exclusively inside or outside cells. The ability to grow in multiple locations may thus help symbionts thrive. We discuss these fitness patterns in light of host-driven factors, whereby hosts exert influence over symbionts to suit their own needs.

Stopover habitat selection drives variation in the gut microbiome composition and pathogen acquisition by migrating shorebirds.

Long-distance host movements play a major regulatory role in shaping microbial communities of their digestive tract. Here, we studied gut microbiota composition during seasonal migration in five shorebird species (Charadrii) that use different migratory (stopover) habitats. Our analyses revealed significant interspecific variation in both composition and diversity of gut microbiome, but the effect of host identity was weak. A strong variation in gut microbiota was observed between coastal and inland (dam reservoir and river valley) stopover habitats within species. Comparisons between host age classes provided support for an increasing alpha diversity of gut microbiota during ontogeny and an age-related remodeling of microbiome composition. There was, however, no correlation between microbiome and diet composition across study species. Finally, we detected high prevalence of avian pathogens, which may cause zoonotic diseases in humans (e.g. Vibrio cholerae) and we identified stopover habitat as one of the major axes of variation in the bacterial pathogen exposure risk in shorebirds. Our study not only sheds new light on ecological processes that shape avian gut microbiota, but also has implications for our better understanding of host-pathogen interface and the role of birds in long-distance transmission of pathogens.

Understanding the factors regulating host-microbiome interactions using Caenorhabditis elegans.

The Human Microbiome Project was a research programme that successfully identified associations between microbial species and healthy or diseased individuals. However, a major challenge identified was the absence of model systems for studying host-microbiome interactions, which would increase our capacity to uncover molecular interactions, understand organ-specificity and discover new microbiome-altering health interventions. Caenorhabditis elegans has been a pioneering model organism for over 70 years but was largely studied in the absence of a microbiome. Recently, ecological sampling of wild nematodes has uncovered a large amount of natural genetic diversity as well as a slew of associated microbiota. The field has now explored the interactions of C. elegans with its associated gut microbiome, a defined and non-random microbial community, highlighting its suitability for dissecting host-microbiome interactions. This core microbiome is being used to study the impact of host genetics, age and stressors on microbiome composition. Furthermore, single microbiome species are being used to dissect molecular interactions between microbes and the animal gut. Being amenable to health altering genetic and non-genetic interventions, C. elegans has emerged as a promising system to generate and test new hypotheses regarding host-microbiome interactions, with the potential to uncover novel paradigms relevant to other systems. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

Unveiling a Shield of Hope: A Novel Multiepitope-Based Immunogen for Cross-Serotype Cellular Defense against Dengue Virus.

Dengue virus (DENV) infection continues to be a public health challenge, lacking a specific cure. Vaccination remains the primary strategy against dengue; however, existing live-attenuated vaccines display variable efficacy across four serotypes, influenced by host serostatus and age, and predominantly inducing humoral responses. To address this limitation, this study investigates a multiepitope-based immunogen designed to induce robust cellular immunity across all DENV serotypes. The chimeric immunogen integrates H-2d specific MHC-I binding T-cell epitopes derived from conserved domains within the DENV envelope protein. Immuno-informatics analyses supported its stability, non-allergenic nature, and strong MHC-I binding affinity as an antigen. To assess the immunogenicity of the multiepitope, it was expressed in murine bone-marrow-derived dendritic cells (BMDCs) that were used to prime mice. In this experimental model, simultaneous exposure to T-cell epitopes from all four DENV serotypes initiated distinct IFNγ-CD8 T-cell responses for different serotypes. These results supported the potential of the multiepitope construct as a vaccine candidate. While the optimization of the immunogen design remains a continuous pursuit, this proof-of-concept study provides a starting point for evaluating its protective efficacy against dengue infection in vivo. Moreover, our results support the development of a multiepitope vaccine that could trigger a pan-serotype anti-dengue CD8 response.

Comparing the gut microbiota of Sichuan golden monkeys across multiple captive and wild settings: roles of anthropogenic activities and host factors

BackgroundCaptivity and artificial food provision are common conservation strategies for the endangered golden snub-nosed monkey (Rhinopithecus roxellana). Anthropogenic activities have been reported to impact the fitness of R. roxellana by altering their gut microbiota, a crucial indicator of animal health. Nevertheless, the degree of divergence in gut microbiota between different anthropogenically-disturbed (AD) R. roxellana and their counterparts in the wild has yet to be elucidated. Here, we conducted a comparative analysis of the gut microbiota across nine populations of R. roxellana spanning China, which included seven captive populations, one wild population, and another wild population subject to artificial food provision.ResultsBoth captivity and food provision significantly altered the gut microbiota. AD populations exhibited common variations, such as increased Bacteroidetes and decreased Firmicutes (e.g., Ruminococcus), Actinobacteria (e.g., Parvibacter), Verrucomicrobia (e.g., Akkermansia), and Tenericutes. Additionally, a reduced Firmicutes/Bacteroidetes ratiosuggested diminished capacity for complex carbohydrate degradation in captive individuals. The results of microbial functional prediction suggested that AD populations displayed heightened microbial genes linked to vitamin and amino acid metabolism, alongside decreased genes associated antibiotics biosynthesis (e.g., penicillin, cephalosporin, macrolides, and clavulanic acid) and secondary metabolite degradation (e.g., naphthalene and atrazine). These microbial alterations implied potential disparities in the health status between AD and wild individuals. AD populations exhibited varying degrees of microbial changes compared to the wild group, implying that the extent of these variations might serve as a metric for assessing the health status of AD populations. Furthermore, utilizing the individual information of captive individuals, we identified associations between variations in the gut microbiota of R. roxellana and host age, as well as pedigree. Older individuals exhibited higher microbial diversity, while a closer genetic relatedness reflected a more similar gut microbiota.ConclusionsOur aim was to assess how anthropogenic activities and host factors influence the gut microbiota of R. roxellana. Anthropogenic activities led to consistent changes in gut microbial diversity and function, while host age and genetic relatedness contributed to interindividual variations in the gut microbiota. These findings may contribute to the establishment of health assessment standards and the optimization of breeding conditions for captive R. roxellana populations.

Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G

The SARS-CoV-2 Omicron variants are notorious for their transmissibility, but little is known about their subgenomic RNA (sgRNA) expression. This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern (non-VOC)-D614G. A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOC-D614G regardless of host gender, age and presence of pneumonia. Remarkably, such profile was lost in samples with low viral load, suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point. A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G. The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load (AUC ​= ​0.91, 95% CI 0.88–0.94), and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient. Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population.

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Effects of Season, Habitat, and Host Characteristics on Ectoparasites of Wild Rodents in a Mosaic Rural Landscape.

Despite the large number of studies on rodent ectoparasites-most of them vectors of epidemiologically important pathogens-infestation patterns remain poorly understood in various ecological contexts, such as the highly patchy agricultural landscapes. We aimed to relate the infestation of rodents to temporal, habitat, and host variables. We assessed the difference in parasite prevalence and mean abundance depending on host sex, age, and body weight, season, and land use intensity. Furthermore, we analysed the effect of host species abundance and the differential responses of parasites in main and minor host species. The field survey was conducted in a rural landscape in southern Transylvania (Romania) between June and September 2010-2011. We live-trapped small mammals, collected the ticks and fleas, and recorded the presence of lice and mites. Overall, we found the same infestation patterns largely reported in the literature: higher prevalence and mean abundance in heavier adult males, significant seasonality and differences among host species, and evidence of the dilution effect. The uniqueness of our study system was the negative effect of the land use intensity on the prevalence and mean abundance of parasites, explained by the highly patchy mosaic landscape.

Newly emerged bumblebees are highly susceptible to gut parasite infection

AbstractOne factor that can affect infection susceptibility is host age, the effects of which vary in a range of ways. For example, susceptibility may increase with age, due to senescence or decrease with age as a result of maturation of the immune system. If certain ages are more susceptible to infection, populations with contrasting demographics, such as same-age cohorts versus a mixture of ages, will exhibit differing disease prevalence. We use the bumblebee, Bombus terrestris, and its interaction with the gut trypanosome Crithidia sp. as a model system to investigate age-related susceptibility in a social insect. Crithidia sp. are widespread and prevalent parasites of bumblebees that are spread between colonies via faeces on flowers when foraging, and within colonies via contact with infected bees and contaminated surfaces and resources. In the field, Bombus spp. live for approximately three weeks. Here, we inoculated bumblebees at 0, 7, 14 and 21 days of age and measured their infection after one week. We also measured the level of gene expression of two antimicrobial peptides important in the defence against Crithidia bombi in bumblebees. We found that younger bumblebees are more susceptible to infection by Crithidia sp. than their older siblings. Specifically, individuals inoculated on their first day of emergence had infection intensities seven days later that were four-fold higher than bees inoculated at 21 days of age. In contrast, the gene expression of two AMPs known to protect against the trypanosome, abaecin and defensin, did not significantly vary with age. These results suggest that age does affect susceptibility to Crithidia sp. infection in B. terrestris. The higher susceptibility of callows may have implications for the susceptibility of colonies at different stages of their lifecycle, due to the contrasting age demography of workers in the colony.

Mosquito ageing modulates the development, virulence and transmission potential of pathogens.

Host age variation is a striking source of heterogeneity that can shape the evolution and transmission dynamic of pathogens. Compared with vertebrate systems, our understanding of the impact of host age on invertebrate-pathogen interactions remains limited. We examined the influence of mosquito age on key life-history traits driving human malaria transmission. Females of Anopheles coluzzii, a major malaria vector, belonging to three age classes (4-, 8- and 12-day-old), were experimentally infected with Plasmodium falciparum field isolates. Our findings revealed reduced competence in 12-day-old mosquitoes, characterized by lower oocyst/sporozoite rates and intensities compared with younger mosquitoes. Despite shorter median longevities in older age classes, infected 12-day-old mosquitoes exhibited improved survival, suggesting that the infection might act as a fountain of youth for older mosquitoes specifically. The timing of sporozoite appearance in the salivary glands remained consistent across mosquito age classes, with an extrinsic incubation period of approximately 13 days. Integrating these results into an epidemiological model revealed a lower vectorial capacity for older mosquitoes compared with younger ones, albeit still substantial owing to extended longevity in the presence of infection. Considering age heterogeneity provides valuable insights for ecological and epidemiological studies, informing targeted control strategies to mitigate pathogen transmission.

Avian trematodes of central European corvids are heterogeneous regarding preferences for host species and age.

Corvids are highly adaptive birds that respond well to anthropogenic changes in their environment. Trematode communities of corvids were studied mainly in the 1950s through 1970s in regularly flooded parts of the Volga River delta in Russia; more recent studies and data from other regions where the corvids are in less contact with postflooding habitats are limited. Data for Corvus corax were lacking. Using our samples obtained from 1963 to 2023, we performed a large-scale analysis of trematode species composition and community structure in Corvus frugilegus, Corvus cornix, C. corax, Coloeus monedula, Pica pica, and Garrulus glandarius; all originated from the Czech Republic. We identified corvids as hosts of mutually overlapping component communities of only a few species of trematodes (Brachylecithum lobatum, Lyperosomum petiolatum, Lyperosomum longicauda, Tamerlania zarudnyi, Urogonimus macrostomus), with the presence of many rare and incidental findings of other trematode species. Only a few species used corvids as their core hosts (L. longicauda and B. lobatum). Trematode component communities in first-year birds included Prosthogonimus cuneatus, Prosthogonimus ovatus, Plagiorchis asperus, and Morishitium dollfusi due to an increased share of insects (intermediate hosts of Prosthogonimus and Plagiorchis) and snails (intermediate hosts of Morishitium) in the diet of juveniles. The trematode component communities of corvid species overlapped but were heterogeneous at the level of host individuals, likely reflecting differences in food sources related to the respective host ages and nesting sites.

Lymphocytic choriomeningitis virus injures the developing brain: effects and mechanisms.

Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the secretions of mice. Most infections of postnatal humans result in mild illness. However, the consequences can be severe when the infection occurs during pregnancy, as the virus crosses the placenta to infect the fetus. LCMV infection of the human fetus can lead to severe neuropathologic effects, including microencephaly, hydrocephalus, focal destructive lesions, and cerebellar hypoplasia. Outcomes among children with congenital LCMV are variable, but most are permanently and severely disabled. The neonatal rat inoculated with LCMV models human prenatal infection. The rat model has demonstrated that effects of LCMV depend on host age at the time of infection. Some effects, including encephalomalacia and neuronal migration disturbances, are immune-mediated and depend on the actions of T-lymphocytes. Other effects, including cerebellar hypoplasia, are virus-mediated and do not depend on T-lymphocytes. Cerebellar neuronal migration disturbances are caused by immune-mediated corruption of Bergmann glia structure. The rat pup inoculated with LCMV is a superb animal model for human congenital infection. All neuropathologic effects observed in human congenital LCMV infection can be recapitulated in the rat model. IMPACT: Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen that can cause serious neurologic birth defects when the infection occurs during pregnancy. The effects of the virus on the developing brain depend strongly on the age of the host at the time of infection. Some of the pathologic effects of LCMV are immune-mediated and are driven by T-lymphocytes, while other pathologic effects are due to the virus itself.