Peptide methionine sulfoxide reductases (Msrs) are
enzymes that repair ROS-damage to
sulfur-containing
amino acids such as
methionine, ensuring functional integrity of cellular
proteins. Here we have shown that unlike the majority of pro- and eukaryotic Msrs, the
peptide methionine sulfoxide reductase (MsrAB) from the human pathobiont Haemophilus influenzae (Hi) is required for the repair of
hypochlorite damage to cell envelope
proteins, but more importantly, we were able to demonstrate that MsrAB plays a role in modulating the host immune response to Hi
infection. Loss of MsrAB resulted in >1000-fold increase in sensitivity of Hi to HOCl-mediated killing, and also reduced biofilm formation and in-biofilm survival. Expression of msrAB was also induced by
hydrogen peroxide and
paraquat, but a Hi2019ΔmsrAB strain was not susceptible to killing by these ROS in vitro. Hi2019ΔmsrAB fitness in
infection models was low, with a 3-fold reduction in intracellular survival in bronchial epithelial cells, increased susceptibility to neutrophil killing, and a 10-fold reduction in survival in a mouse model of lung
infection. Interestingly,
infection with Hi2019ΔmsrAB led to specific changes in the antibacterial response of human host cells, with genes encoding
antimicrobial peptides (BPI, CAMP) upregulated between 4 and 9 fold compared to
infection with Hi2019WT, and reduction in expression of two
proteins with antiapoptotic functions (BIRC3, XIAP). Modulation of host immune responses is a novel role for an
enzyme of this type and provides first insights into mechanisms by which MsrAB supports Hi survival in vivo.