In the temperate regions, seasonal influenza virus outbreaks correlate closely with decreases in humidity. While low ambient humidity is known to enhance viral transmission, its impact on host ...response to influenza virus infection and disease outcome remains unclear. Here, we showed that housing Mx1 congenic mice in low relative humidity makes mice more susceptible to severe disease following respiratory challenge with influenza A virus. We find that inhalation of dry air impairs mucociliary clearance, innate antiviral defense, and tissue repair. Moreover, disease exacerbated by low relative humidity was ameliorated in caspase-1/11–deficient Mx1 mice, independent of viral burden. Single-cell RNA sequencing revealed that induction of IFN-stimulated genes in response to viral infection was diminished in multiple cell types in the lung of mice housed in low humidity condition. These results indicate that exposure to dry air impairs host defense against influenza infection, reduces tissue repair, and inflicts caspase-dependent disease pathology.
Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ...ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.
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•Zika virus replicates in the vaginal tract of wild-type virgin and pregnant mice•Innate RNA sensors and type I interferons control vaginal Zika virus replication•Vaginal Zika virus infection in early pregnancy leads to fetal growth restriction•Vaginal Zika virus infection of pregnant dams leads to fetal brain infection
Vaginal mucosa is permissive to the replication of Zika virus, and infection through this route can lead to fetal brain infection even in mice with an intact immune system.
Neutrophil activation and the formation of neutrophil extracellular traps (NETs) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE). Here we report that the expression of ...an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and correlated with autoantibody levels and higher interferon status. Induction of ERV-K102 in SLE negatively correlated with the expression of epigenetic silencing factors. Anti-ERV-K102 IgG levels in SLE plasma correlated with higher interferon stimulated gene expression, and further promoted enhanced neutrophil phagocytosis of ERV-K102 envelope protein through immune complex formation. Finally, phagocytosis of ERV-K102 immune complexes resulted in the formation of NETs consisting of DNA, neutrophil elastase, and citrullinated histone H3. Together, we identified an immunostimulatory ERV-K envelope protein that in an immune complex with SLE IgG is capable of activating neutrophils.
Breakthrough findings in the clinical and preclinical development of tuberculosis (TB) vaccines have galvanized the field and suggest, for the first time since the development of bacille ...Calmette-Guérin (BCG), that a novel and protective TB vaccine is on the horizon. Here we highlight the TB vaccines that are in the development pipeline and review the basis for optimism in both the clinical and preclinical space. We describe immune signatures that could act as immunological correlates of protection (CoP) to facilitate the development and comparison of vaccines. Finally, we discuss new animal models that are expected to more faithfully model the pathology and complex immune responses observed in human populations.
Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, ...but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (
) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the
background (
) and found that
mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from
mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (
) mice. However, intravaginal ERV treatment did not protect
mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in
mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.
Abstract
Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ...ERVs, but whether ERVs contribute to antiviral immunity is not known. Here we used herpes simplex virus type 2 (HSV-2) infection and found that mice deficient in Toll-like receptor 7 (Tlr7−/−) that have high systemic levels of infectious ERVs are resistant to intravaginal HSV-2 infection compared with wildtype C57BL/6 (B6) mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7−/− background (Emv2−/−Tlr7−/−) and found that Emv2−/−Tlr7−/− mice are no longer protected against HSV-2. Intravaginal application of purified ERVs prior to HSV-2 infection in both B6 and highly susceptible interferon-alpha receptor-deficient (Ifnar1−/−) mice delayed disease course. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7−/− mice or B6 mice treated with purified ERVs. Instead, we observed enhanced expression of epithelial tight junction protein, E-cadherin, in the vaginal epithelium of ERV-treated B6 mice. Similar increase in tight junction proteins was observed in Tlr7−/− but not in the Emv2−/−Tlr7−/− mice. Together, our results showed that IFN-independent modulation of the vaginal epithelium by ERVs protects mice against vaginal HSV-2 infection and lowers disease burden.
Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host ...resistance against ZIKV, and IFN-α/β receptor (IFNAR)-deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (
) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged
dams mated with
sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (
) or do not express IFNAR (
) within the same uterus. Virus replicated to a higher titer in the placenta of
than within the
concepti. Yet, rather unexpectedly, we found that only
fetuses were resorbed after ZIKV infection during early pregnancy, whereas their
littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.
A generalized plasma model with inertial warm ions, inertialess iso-thermal electrons, super-thermal electrons and positrons is considered to theoretically investigate the modulational instability ...(MI) of ion-acoustic waves (IAWs). A standard nonlinear Schrödinger equation is derived by applying the reductive perturbation method. It is observed that the stable domain of the IAWs decreases with ion temperature but increases with electron temperature. It is also found that the stable domain increases by increasing (decreasing) the electron (ion) number density. The present results will be useful in understanding the conditions for MI of IAWs which are relevant to both space and laboratory plasmas.
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