MAIT cells are activated in acute Dengue virus infection and after in vitro Zika virus infection

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) are members of the Flaviviridae and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading to death in some cases. ZIKV is now linked with Guillain-Barré syndrome and fetal malformations including microcephaly and developmental disorders (congenital Zika syndrome). The protective and pathogenic roles played by the immune response in these infections is unknown. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells with potent anti-bacterial activity. MAIT cells have also been postulated to play a role in the immune response to viral infections. In this study, we evaluated MAIT cell frequency, phenotype, and function in samples from subjects with acute and convalescent DENV infection. We found that in acute DENV infection, MAIT cells had elevated co-expression of the activation markers CD38 and HLA-DR and had a poor IFNγ response following bacterial stimulation. Furthermore, we found that MAIT cells can produce IFNγ in response to in vitro infection with ZIKV. This MAIT cell response was independent of MR1, but dependent on IL-12 and IL-18. Our results suggest that MAIT cells may play an important role in the immune response to Flavivirus infections.

Understanding the Role of Mucosal-Associated Invariant T-Cells in Non-human Primate Models of HIV Infection

“…Similar findings have also been made in mice following influenza infection ( 11 ), as well as in vitro with hepatitis C ( 7 ), influenza ( 12 ), and zika virus ( 8 ). Virus-induced MAIT cell activation is mediated through TCR-independent pathways, as shown for influenza ( 7 , 12 ), dengue ( 7 ), hepatitis C ( 7 ), or zika virus ( 8 ) exposure in vitro . This stands in contrast to MAIT cell stimulation with paraformaldehyde fixed E. coli , which is blocked by treatment with an anti-MR1 blocking antibody.…”

“…Viral replication cycles do not involve vitamin B synthesis pathways, which are necessary for TCR-dependent MAIT cell activation. Multiple studies have shown increased MAIT cell activation in patients with active viral infections, including dengue ( 7 , 8 ), influenza ( 7 ), chronic hepatitis B ( 9 ), hepatitis C ( 7 ), and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) ( 10 ). Similar findings have also been made in mice following influenza infection ( 11 ), as well as in vitro with hepatitis C ( 7 ), influenza ( 12 ), and zika virus ( 8 ).…”

“…Multiple studies have shown increased MAIT cell activation in patients with active viral infections, including dengue ( 7 , 8 ), influenza ( 7 ), chronic hepatitis B ( 9 ), hepatitis C ( 7 ), and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) ( 10 ). Similar findings have also been made in mice following influenza infection ( 11 ), as well as in vitro with hepatitis C ( 7 ), influenza ( 12 ), and zika virus ( 8 ). Virus-induced MAIT cell activation is mediated through TCR-independent pathways, as shown for influenza ( 7 , 12 ), dengue ( 7 ), hepatitis C ( 7 ), or zika virus ( 8 ) exposure in vitro .…”

Tissue-Resident Innate and Innate-Like Lymphocyte Responses to Viral Infection

“…MAIT cells robustly respond to IL-12 and IL-18 stimulation, which produces IFN-γ, TNF-α, and IL-17 that can enhance innate and adaptive B cell antibody responses [54,55]. In humans, MAIT cells have been implicated in the antiviral response to dengue virus, hepatitis C virus, influenza virus, and Zika virus in response to IL-12 and IL-18 [56,57]. This evidence is further supported by evidence from MAIT cell deficient MR1 −/− mice that display increased weight loss and mortality during H1N1 infection [58].…”

The Immune Modulating Properties of Mucosal-Associated Invariant T Cells

“…Viruses are unable to synthesize vitamin B2 metabolites and cannot elicit TCR-dependent MAIT cell activation. Nevertheless, viral infections can elicit MAIT cell activation in a TCR-independent manner, through the release of different cytokines such as IL-12 and IL-18 ( 17 , 18 ). MAIT cell activation results in the production of a variety of chemokines and pro-inflammatory cytokines, associated with both Th1 (IFN-γ and TNF-α) ( 16 , 19 ) and Th17 immunity (IL-17 and IL-22) ( 20 ), but in certain tissues or upon prolonged stimulation MAIT cells can also release IL-10 and IL-13 ( 21 , 22 ).…”