Immune checkpoints are suppressed during pregnancy following influenza A virus infection

Influenza A virus (IAV) infection is a major health risk during pregnancy. Although vaccination and antiviral agents are widely used and reduce IAV-induced symptoms, they are not sufficient to control IAV infections in pregnancy, especially during pandemics. Respiratory viruses like IAV exploit immune alterations that occur during pregnancy, including the upregulation of immune checkpoint proteins (ICPs) like programmed death ligand-1 (PDL1), programmed cell death receptor 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). We hypothesize that blocking expression of PDL1 on innate immune cells will improve maternal immunity following IAV infection. We used murine models of IAV infection during pregnancy with and without treatment with the immune checkpoint inhibitor (ICI), a-PDL1. Pregnant and nonpregnant mice were infected with mouse-adapted IAV (A/PR/8) and assessed at 3 days post infection (3 dpi). Lung cells were analyzed using flow cytometry. Lung mRNA expression of inflammatory and antiviral markers and histology was measured. Protein concentrations of inflammatory and antiviral markers, as well as viral titers were measured from lung bronchiolar lavage fluid (BALF). Lung function was also assessed. Following IAV infection, immune cells from pregnant mice had significant increases in the ICPs, PDL1, PD1, and CTLA4. a-PDL1 treatment effectively suppressed these ICPs and increased the activation marker, CD86. a-PDL1 treatment also reduced lung inflammatory cell infiltration and viral titers, increased antiviral responses, and improved lung function. Overall, IAV infection in pregnancy activates key inhibitory ICPs, leading to worsened disease outcomes. a-PDL1 treatment during IAV infection in pregnancy is an effective method to reduce ICP expression and improve overall immune cell responses.<b>NEW & NOTEWORTHY</b> Influenza infection worsens disease outcomes during pregnancy; however, treatment with anti-PDL1 can restore immune function during pregnancy.