The DmsABC Sulfoxide Reductase Supports Virulence in Non-typeable Haemophilus influenzae

Abstract

Although molybdenum-containing enzymes are well-established as having a key role in bacterial respiration, it is increasingly recognized that some may also support bacterial virulence. Here, we show that DmsABC, a putative dimethylsulfoxide (DMSO) reductase, is required for fitness of the respiratory pathogen Haemophilus influenzae (Hi) in different models of infection. Expression of the dmsABC operon increased with decreasing oxygen availability, but despite this, a Hi2019ΔdmsA strain did not show any defects in anaerobic growth on chemically defined medium (CDM), and viability was also unaffected. Although Hi2019ΔdmsA exhibited increased biofilm formation in vitro and greater resistance to hypochlorite killing compared to the isogenic wild-type strain, its survival in contact with primary human neutrophils, in infections of cultured tissue cells, or in a mouse model of lung infection was reduced compared to Hi2019WT. The tissue cell infection model revealed a two-fold decrease in intracellular survival, while in the mouse model of lung infection Hi2019ΔdmsA was strongly attenuated and below detection levels at 48 h post-inoculation. While Hi2019WT was recovered in approximately equal numbers from bronchoalveolar lavage fluid (BALF) and lung tissue, survival of Hi2019ΔdmsA was reduced in lung tissue compared to BALF samples, indicating that Hi2019ΔdmsA had reduced access to or survival in the intracellular niche. Our data clearly indicate for the first time a role for DmsABC in H. influenzae infection and that the conditions under which DmsABC is required in this bacterium are closely linked to interactions with the host.

TheHaemophilus influenzaein vivo gene expression reveals major clues about bacterial central metabolism, acquisition of trace elements, and other essential pathways during infection of the human lung

“…Another MetSO reducing enzyme, DMSO-reductase, has in previous studies been reported to be essential for H. influenzae virulence, as mutant strains lacking the dmsA gene showed reduced fitness compared to the wild type (77). Remarkably, we found the DMSO reductase-involved genes dmsA and dmsD to be highly downregulated in vivo .…”

HMSS2: An advanced tool for the analysis of sulphur metabolism, including organosulphur compound transformation, in genome and metagenome assemblies

“…These compounds not only represent a vast reservoir of sulphur but can also be used by prokaryotes as a sources of energy and carbon (Moran & Durham, 2019). Understanding the mechanisms and ecological interactions of prokaryotes in the organic sulphur cycle is of great importance because the decomposition of organic sulphur compounds affects human health, bacterial virulence in infection (Dhouib et al, 2021), global warming, bioremediation processes such as wastewater treatment (Schäfer et al, 2010), and is linked to the biogeochemical cycling of sulphur between habitats (Koch & Dahl, 2018).…”

“…cycle is of great importance because the decomposition of organic sulphur compounds affects human health, bacterial virulence in infection (Dhouib et al, 2021), global warming, bioremediation processes such as wastewater treatment (Schäfer et al, 2010), and is linked to the biogeochemical cycling of sulphur between habitats (Koch & Dahl, 2018). Sulphonated compounds can range from small size with only a C 1 carbon skeleton up to sulphonated lipids with long-chain alkanes, amino acids such as cysteine, or sulphur-containing cofactors with complex structures such as lipoate (Boden & Hutt, 2019;Goddard-Borger & Williams, 2017;Moran & Durham, 2019).…”

The Peptide Methionine Sulfoxide Reductase (MsrAB) of Haemophilus influenzae Repairs Oxidatively Damaged Outer Membrane and Periplasmic Proteins Involved in Nutrient Acquisition and Virulence

“…We have recently characterized three enzymes involved in MetSO reduction in the H. influenzae periplasm, the molybdenum enzymes DmsABC and MtsZ and the MsrAB methionine sulfoxide reductase that contains both an MsrA and MsrB domain [ 16 , 17 , 18 , 19 ]. Both of the molybdenum-containing enzymes were able to reduce free MetSO; however, expression levels of DmsABC were significantly lower than for MtsZ, which appears to be the major molybdenum-dependent methionine sulfoxide reductase in H. influenzae strain Hi2019 [ 17 , 19 ].…”