Haemophilus influenzae (Hi) is a highly prevalent human respiratory pathobiont that is associated with recurring, acute, and chronic diseases in children and adults such as otitis media, pneumonia, chronic obstructive pulmonary disease, and asthma. The molecular basis for persistence and recurrence of Hi infections is not well understood but is likely linked to Hi metabolic properties and its increasingly recognized ability to survive intracellularly in host cells. Here we have investigated the role of nutritional virulence for Hi persistence and access to different host cell niches.
Hi preferred growth substrates were shown to be highly adapted to human epithelial surfaces and included lactate, pentoses and nucleosides, but not glucose that is typically used for Hi in vitro growth. Lactate utilization in Hi involved three enzymes, with the LldD L-lactate dehydrogenase driving use of lactate as a carbon source, while the two D-lactate dehydrogenases, Dld and LdhA, were involved in redox balancing. Colonization and survival of Hi in the intracellular space was directly linked to substrate utilization, with L-lactate being required for intracellular survival, while guanine de novo biosynthesis affected both extra- and intra-cellular survival in several models of infection, including mice and primary normal human nasal epithelia.
Pathogenic bacteria can also affect host responses to infection via the excretion of particular metabolites, and accumulation of major metabolic end-products such as the immunometabolite acetate in the case of Hi. Acetate had anti-inflammatory effects on cultured human tissue cells in the presence of live but not heat-killed Hi. Our work provides evidence of the critical role of metabolic processes for persistence of Hi inside host cells and the immunomodulatory potential of Hi metabolic end-products.