CD8 tissue-resident memory T cells bridge the gap between humoral and cell-mediated immunity.

Tissue-resident memory T (TRM) cells exert antiviral effects in situ using a variety of cell-intrinsic mechanisms. In this issue of Mucosal Immunology, Rosato and colleagues demonstrate that mucosal CD8 TRM cells can also facilitate the extravasation of antibodies with neutralizing capacities by modulating transcytotic receptors and vascular permeability, thus revealing a new mechanism by which TRM cells modulate humoral responses and protect the host from incoming pathogens.

NK cell-derived extracellular granzyme B drives epithelial ulceration during HSV-2 genital infection.

Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes.

A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection.

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.

Herpes simplex virus (HSV) is a human pathogen that causes genital herpes, an incurable disease that results in recurrent sores and inflammation. Infection with HSV induces a strong antiviral immune response, which results in large numbers of immune cells arriving at these lesions. But while some of these cells help to control viral replication, others might contribute to the inflammation that drives the disease. One of the first immune cells to respond to infection are neutrophils. Although neutrophils are generally protective, especially against bacteria and fungi, they have also been implicated in tissue damage and severe inflammation during viral infections. But what determines whether a neutrophil will help to fight off an infection or increase disease severity is still an open question. To investigate this, Lebratti, Lim et al. studied mice that had been infected with the genital herpes virus HSV-2, which is known to cause significant amounts of inflammation in mice. The experiments revealed that a signaling molecule called type I interferon, which is thought to be antiviral, causes neutrophils at the site of the infection to produce proteins, such as IL-18, which trigger an inflammatory reaction. Lebratti, Lim et al. found that type I interferon and IL-18 had shifting roles during the course of infection. In the early stages, both molecules had a protective effect, confirming results from previous studies. However, as the infection progressed, sustained levels of type I interferon signaling in neutrophils led to excess amounts of IL-18. Lebratti, Lim et al. discovered that blocking interferon signaling or decreasing the levels of IL-18 later during infection unexpectedly reduced the severity of the disease and resulted in less genital tissue damage. Further experiments also showed that mice infected with another genital herpes virus called HSV-1 did not experience sustained levels of type I interferon. This may explain why this virus causes less severe disease in mice. Understanding how the immune system reacts to viruses could reveal new targets for treatments of genital herpes. At the moment, there is little information about IL-18 production during genital herpes in humans. So, the next step is to see whether neutrophils behave in the same way and whether IL-18 can be detected during human disease. It is possible that the same immune components could promote disease in other infections too. If so, this work may help uncover new drug targets for other viral diseases.

Fungal Symbionts Produce Prostaglandin E2 to Promote Their Intestinal Colonization.

Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 (PGE2), but the physiological significance of fungus-derived PGE2 remains elusive. Here we report that a C. albicans mutant deficient in PGE2 production suffered a loss of competitive fitness in the murine gastrointestinal (GI) tract and that PGE2 supplementation mitigated this fitness defect. Impaired fungal PGE2 production affected neither the in vitro fitness of C. albicans nor hyphal morphogenesis and virulence in either systemic or mucosal infection models. Instead, fungal production of PGE2 was associated with enhanced fungal survival within phagocytes. Consequently, ablation of colonic phagocytes abrogated the intra-GI fitness boost conferred by fungal PGE2. These observations suggest that C. albicans has evolved the capacity to produce PGE2 from arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous mechanisms might undergird host-microbe interactions of other symbiont fungi.