Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

Normalizing the environment recapitulates adult human immune traits in laboratory mice

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS. Description Stronger evidence for viral connection Multiple sclerosis is a chronic demyelinating disease of the central nervous system. The underlying cause of this disease is not known, but Epstein-Barr virus is thought to be a possible culprit. However, most people infected with this common virus do not develop multiple sclerosis, and it is not feasible to directly demonstrate causation of this disease in humans. Using data from millions of US military recruits monitored over a 20-year period, Bjornevik et al. determined that Epstein-Barr virus infection greatly increased the risk of subsequent multiple sclerosis and that it preceded the development of disease, supporting its potential role in the pathogenesis of multiple sclerosis (see the Perspective by Robinson and Steinman). —YN Epstein-Barr virus infection precedes symptoms and biomarkers of multiple sclerosis and markedly increases disease risk.

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms tha...

The Immunology of Epstein-Barr Virus–Induced Disease

https://eprints.ncl.ac.uk/file_store/production/276471/976D2277-7817-45AD-8067-239E10A4CDA2.pdf

Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2.

Primary Epstein-Barr virus infection

(See the editorial commentary by Rickinson and Fox, on pages 6–8.)

Epstein-Barr virus (EBV) was discovered in 1964 [1] and conclusively linked to infectious mononucleosis in 1968 [2]. More than 4 decades later, however, the incidence and risk factors for acquisition and correlates of severity of primary EBV infection are incompletely understood. The prevalence of EBV antibodies varies widely by age and geographic location [3–5], and the inference has been that the later in life EBV infection is acquired, the more likely it will be symptomatic [6]. However, the proportion of symptomatic infections in any age group is not well described. Furthermore, infectious mononucleosis has been postulated to be an immunopathologic disease whose symptoms are caused by the CD8+ response to the virus rather than to the virus per se. Indeed, CD8+ lymphocytosis—not viremia—was associated with symptomatic disease in a previous study of primary EBV infection [7].

An accurate assessment of the burden of disease attributable to primary EBV infection is an important component in the development of a prophylactic vaccine or antiviral therapy. This information can only be obtained by a prospective study, which we were able to perform because we had access to >4000 resident freshmen on the campus of the University of Minnesota, whose rate of natural infection is relatively high [8]. This report describes our findings in students from 2 freshman classes followed prospectively throughout their undergraduate years with frequent reporting of health histories, clinical monitoring, quantitative virologic testing, and immunologic testing. We measured the following factors to define their range, kinetics, and correlation with disease severity during primary infection: blood and oral viral loads; CD8+, CD4+, and natural killer (NK) cell numbers; and T-cell activation markers.

Behavioral, Virologic, and Immunologic Factors Associated With Acquisition and Severity of Primary Epstein–Barr Virus Infection in University Students

We performed an intensive prospective study designed to obtain as much data as possible on the incubation and early illness periods of primary Epstein–Barr virus (EBV) infection. Undergraduate students who lacked EBV antibody and oral EBV DNA (EBV-naive) were seen every 2 weeks during their freshman year. Clinical and behavioral data, oral washes and venous blood were obtained. EBV antibodies were quantified by enzyme immunoassay and viral loads by PCR. During a median 8 months of observation, 14/85 subjects experienced primary EBV infections (24 cases/100 person-years). The only significant risk factor for acquisition of EBV infection was deep kissing (P=0.02). Eleven subjects had infectious mononucleosis with a median duration of 21 days. Two subjects were hospitalized. Infections were initially identified in 12 subjects by finding EBV DNA in oral cells before onset of symptoms and in 2 subjects by symptom reporting. EBV DNA and viral capsid antigen (VCA) IgM and gp350 IgG antibodies were present in the blood before onset of illness. To provide a more robust evaluation of primary EBV infection in undergraduate university students, we combined data on risk factors and antibody responses from this and an earlier study that used the exact same clinical and laboratory methods. The observation that the only significant risk factor for acquisition of EBV infection was deep kissing was confirmed. Most importantly, higher amounts of gp350 antibody correlated significantly with a lower severity of infectious mononucleosis (P<0.0001), which strengthens the rationale for a gp350-based prophylactic EBV vaccine.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1038/cti.2016.48

Julie A. Ed

Papers

Behavioral, Virologic, and Immunologic Factors Associated With Acquisition and Severity of Primary Epstein–Barr Virus Infection in University Students

Prospective studies of infectious mononucleosis in university students.