Regulation of immune responses during viral infection is critical to preventing the development immunopathology that impairs host survival. NK cells are well-known for their antiviral functions that promote viral clearance, however their roles in limiting immune-mediated pathology are still unclear. Using a mouse model for genital herpes simplex virus type 2 infection, we find that NK cell derived-IFN-γ directly counteracts IL-6 mediated matrix metalloproteases (MMP) activity in macrophages to limit MMP-mediated tissue damage. Our findings uncover a key immunoregulatory function of NK cells during host-pathogen interactions that highlight the potential of NK cell therapy for treatment of severe viral infections.

Background: Live attenuated (LA) vaccines alter immune functions and are associated with beneficial outcomes. We previously demonstrated that yellow fever virus vaccine (LA-YF-Vax) dampens T cell receptor (TCR) signaling in vitro via an RNA-based mechanism. We examined subjects before and after LA-YF-Vax to assess TCR-mediated functions in vivo. Methods: Sera and peripheral blood mononuclear cells (PBMCs) were obtained before and after LA-YF-Vax (+/-additional vaccines) or quadrivalent influenza vaccine (QIV). TCR-mediated activation was determined by IL-2 release or phosphorylation of the lymphocyte-specific-Src-kinase. TCR-regulating phosphatase (PTPRE) expression was also measured. Results: Compared to pre-vaccination, LA-YF-Vax recipient PBMCs demonstrated transient reduction in IL-2 release following TCR-stimulation and PTPRE levels, unlike QIV control subjects. YFV was detected in (8/14) following LA-YF-Vax. Following incubation of healthy donor PBMCs in serum-derived extracellular vesicles (EVs) prepared from LA-YF-Vax recipients, TCR signaling and PTPRE levels were reduced post-vaccination, even in subjects without detectable YFV RNA. Conclusions: LA-YF-Vax reduces TCR functions and PTPRE levels following vaccination. EVs from serum recapitulated this effect in healthy cells. This likely contributes to the reduced immunogenicity for heterologous vaccines following LA-YF-Vax administration. Identification of specific immune mechanisms related to vaccines should contribute to understanding of the “off target”, beneficial effects of live vaccines.

Human papillomavirus viral load (HPV VL) is associated with persistence, which increases cervical cancer risk. The bivalent vaccine protects against oncogenic HPV16/18 and cross-protects against several non-vaccine types. We examined the effect of two-dose (2D) and three-dose (3D) vaccination on HPV prevalence and viral load in clearing (CIs) and persistent infections (PIs), 6y and 12y post-vaccination, respectively. Vaginal swabs collected from HPV Among Vaccinated And Non-vaccinated Adolescents (HAVANA, 3D-eligible) and HAVANA-2 (2D-eligble) participants were genotyped for HPV with the SPF₁₀-DEIA-LiPA₂₅. HPV VL was measured with type-specific qPCRs. HPV16, 18, 31, 33 and 45 CI and/or PI prevalence and HPV16, 18, and 31 VLs in CIs were significantly reduced in 3D vaccinated women compared to unvaccinated women. Except for HPV11 and HPV59 CIs, no significant VL differences were observed among vaccinated women, ≤6y and >6y post-vaccination. Infection numbers were low in 2D-eligible women, with no HPV16 and 18 in vaccinated women. No VL differences for the remaining types were found. 3D vaccination reduces HPV prevalence in CIs and PIs and decreases HPV VLs in CIs, 12y post-vaccination for vaccine and several non-vaccine types. 2D-eligible women had low infection numbers, with no HPV16/18 among vaccinated women.

Progressive multifocal leukoencephalopathy (PML) is a severe neurological condition caused by reactivation of JC polyomavirus (JCPyV) in immunosuppression. Asymptomatic JCPyV persists in peripheral tissues. Upon reactivation, neurotropic rearrangements may emerge, and the virus gains access to the brain. To assess the mechanisms of PML pathogenesis, brain tissue material from PML patients was collected for small RNA sequencing. Upregulation of eight microRNAs (miRNAs) in PML brain was validated using quantitative microRNA PCR. Bioinformatics tools were utilized to identify major associations of the upregulated miRNAs: neuroinflammation and blood-brain-barrier disruption. The results indicate involvement of human miRNA regulation in PML pathogenesis.

Women and underrepresented in medicine applicants value climate for diversity when selecting graduate medical education training programs. Climate may not be accurately represented during virtual recruitment. Optimizing program websites may help overcome this barrier. We reviewed websites for adult infectious disease (ID) fellowships that participated in the 2022 National Resident Matching Program (NRMP) Match for emphasis on diversity, equity and inclusion (DEI). Fewer than half expressed DEI language in their mission statement or had a dedicated DEI statement or webpage. Programs should consider emphasizing their commitment to DEI prominently on their websites, which may help recruit candidates from diverse backgrounds.

Convalescent plasma (CP) treatment of COVID-19 has shown significant therapeutic effect when administered early (e.g. Argentinian trial showing reduced hospitalisation) but has in general been ineffective (e.g. REMAP-CAP trial without improvement during hospitalisation). To investigate whether the differences in CP used could explain the different outcomes, we compared neutralising antibodies, anti-spike IgG and avidity of CP used in the REMAP-CAP and Argentinian trials and in convalescent vaccinees. We found no difference between the trial plasmas emphasising initial patient serostatus as treatment efficacy predictor. By contrast, vaccinee convalescent plasma showed significantly higher titres and avidity, being preferable for future CP-treatment.

Background: Testing and contact tracing (CT) can interrupt transmission chains SARS-CoV-2. Whole genome sequencing (WGS) can potentially strengthen these investigations and provide insights on transmission. Methods: We included all laboratory-confirmed COVID-19 cases diagnosed between June 4 to July 26, 2021, in a Swiss canton. We defined CT clusters based on epidemiological links reported in the CT data and genomic clusters as sequences with no single nucleotide polymorphism (SNP) differences between any two pairs of sequences being compared. We assessed the agreement between CT clusters and genomic clusters. Results: Of 359 COVID-19 cases, 213 were sequenced. Overall, agreement between CT and genomic clusters was low (Kappa coefficient=0.13). Out of 24 CT clusters with at least two sequenced samples, 9 (37.5%) were also linked based on genomic sequencing but in four of these, WGS found additional cases in other CT clusters. Household was most often reported source of infection (101, 28.1%) and home addresses coincided well with CT clusters: In 44 out of 54 CT clusters containing at least two cases (81.5%), all cases of the cluster had the same home address. However, only a quarter of household transmission was confirmed by WGS (6 out of 26 genomic clusters, 23.1%). A sensitivity analysis using ≤1 SNP differences to define genomic clusters resulted in similar results. Conclusions: WGS data supplemented epidemiological CT data, supported the detection of potential additional clusters missed by CT, and identified misclassified transmissions and sources of infection. Household transmission was overestimated by CT.

Diarrhea is the second leading causing of death in children <5 worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics on diarrhea. Using three well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies. For diarrhea frequency, we identified two genome-wide significant loci associated with not having any diarrhea on chromosome 21, within the non-coding RNA AP000959 (C allele OR=0.31, P=4.01x10^-8) and on chromosome 8, within SAMD12 (T allele OR=0.35, P=4.74x10^-7). For duration of diarrhea, we identified two loci associated with no diarrhea including the same locus on chromosome 21 (C allele OR=0.31, P=1.59x10^-8) and another locus on chromosome 17, near WSCD1 (C allele OR=0.35, P=1.09x10^-7). These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.

Genome-wide association studies have identified several risk alleles for early childhood asthma, particularly in the 17q21 locus and in the cadherin-related family member 3 (CDHR3) gene. Contribution of these alleles to the risk of acute respiratory tract infections (ARI) in the early childhood is unclear. We analyzed data from the STEPS birth-cohort study of unselected children and the VINKU and VINKU2 studies on children with severe wheezing illness. Genome-wide genotyping was performed on 1011 children. We analyzed the association between 11 pre-selected asthma risk alleles and the risk of ARIs and wheezing illnesses of various viral etiologies. The asthma risk alleles in CDHR3, GSDMA, and GSDMB were associated with an increased rate of ARIs (for CDHR3, incidence rate ratio [IRR], 1.06; 95% CI, 1.01-1.12; P=0.02), and risk allele in CDHR3 gene with rhinovirus infections (IRR, 1.10; 95% CI, 1.01-1.20, P=0.03). Asthma risk alleles in GSDMA, GSDMB, IKZF3, ZPBP2, and ORMDL3 genes were associated with wheezing illnesses in early childhood, especially rhinovirus-positive wheezing illnesses. Asthma risk alleles were associated with an increased rate of ARIs and an increased risk of viral wheezing illnesses. Non-wheezing and wheezing ARIs and asthma may have shared genetic risk factors.

Background: Targeted surveillance allows public health authorities to implement testing and isolation strategies when diagnostic resources are limited, and can be implemented via the consideration of social network topologies. Yet, it remains unclear how to implement such surveillance and control when network data are unavailable. Methods: We evaluated the ability of socio-demographic proxies of degree centrality to guide prioritized testing of infected individuals compared to known degree centrality. Proxies were estimated via readily-available socio-demographic variables (age, gender, marital status, educational attainment, and household size). We simulated SARS-CoV-2 epidemics via a SEIR individual-based model on two contact networks from rural Madagascar to further test the applicability of these findings to low-resource contexts. Results: Targeted testing using socio-demographic proxies performed similarly to targeted testing using known degree centralities. At a low testing capacity, using the proxies reduced the infection burden by 22-33% while using 20% fewer tests, compared to random testing. By comparison, using known degree centrality reduced the infection burden by 31-44% while using 26-29% fewer tests. Conclusions: We demonstrate that incorporating social network information into epidemic control strategies is an effective countermeasure to low testing capacity and can be implemented via socio-demographic proxies when social network data are unavailable.