B cells are the predominant mediators of early systemic viral dissemination during rectal LCMV infection

Abstract

Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node. Here, we show that rectal infection with LCMV triggers type I/III interferon responses, followed by innate immune activation and lymphocyte recruitment to the colon. In contrast to vaginal exposure, innate immunity controls LCMV replication in the colon, but virus rapidly disseminates systemically. Virus-induced inflammation promotes the recruitment of LCMV target cells to the colon followed by splenic viral dissemination by infected B cells, and to a lesser extent by CD8 T cells. These findings demonstrate major immunological differences between vaginal and rectal exposure to the same viral pathogen, highlighting unique risks associated with each of these common routes of sexual viral transmission.

Lack of Sprouty 1 and 2 enhances survival of effector CD8 + T cells and yields more protective memory cells

“…Flow Cytometry. Cell counts for prepared single-cell suspensions were determined as previously described (47). After blocking Fc receptors with anti-CD16 + CD32, 1 × 10 6 cells from single-cell suspensions were incubated with a mixture of fluorescence-conjugated anti-mouse antibodies for 30 min at 4°C.…”

“…To determine if the absence of Spry1/2 alters the in vivo functionality of effector T cells to control viral infection, we used our LCMV intrarectal (i.rec.) infection model (47). In the i.rec.…”

Low expression of RNA sensors impacts Zika virus infection in the lower female reproductive tract

“…Significantly, vaginal exposure in mice during early pregnancy or sexual transmission leads to fetal brain infection and pathology 18,21,22 . We have shown that antiviral innate and adaptive immunity against lymphocytic choriomeningitis virus (LCMV- Arenaviridae ) and ZIKV are uniquely dampened in the vaginal tissue, whereas infections of other mucosal surfaces, such as the uterus 17 or the colon 23 induce a vigorous canonical antiviral immune response. Since this diminished response in the vaginal mucosa is not common to all sexually transmitted pathogens 24,25 , we hypothesized that the dampened immunity against both LCMV and ZIKV in the vaginal tissue may be due to sub-optimal innate sensing of viral RNA.…”

Segmented, Negative-Sense RNA Viruses of Humans: Genetic Systems and Experimental Uses of Reporter Strains

“…In addition to the aforementioned type of genes that have been introduced into rLCMV systems, an important usage of rLCMV, especially the r3LCMV systems, has been the development of a variety of rLCMVs that stably express nonfluorescent reporters such as CAT (104,115,116) as well as fluorescent reporter genes. These include the replacement of wild-type viral GPC or NP segments with eGFP (104,106,107,(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124), teal fluorescent protein (125), mCherry (126,127), or ZsGreen (128)(129)(130). Not only do these reporters allow for assessment of viral replication in less time than is needed for traditional plaque assays, but also they have been a powerful tool in highthroughput screening approaches used to identify small-molecule antivirals (131), identification of receptors required for host cell infection (126), and the discovery that LCMV can cause long-term immune dysfunction months after infection (125), among many other important discoveries.…”