Highlights d Hypoxia curtails C. burnetii replication in macrophages without reducing bacterial viability d Hypoxia induces robust HIF1a accumulation in infected macrophages d HIF1a reduces STAT3 activation and citrate availability in infected hypoxic macrophages d Low levels of TCA metabolites impede C. burnetii replication in macrophages
Bacteria can cause life-threatening infections, such as pneumonia, meningitis or sepsis. Antibiotic therapy is a mainstay of treatment, although antimicrobial resistance has drastically increased over the years. Unfortunately, safe and effective vaccines against most pathogens have not yet been approved, thus developing alternative treatments is important. We analyzed the efficiency of FH6-7/Fc, a novel antibacterial immunotherapeutic protein against the gram-positive bacterium Streptococcus pyogenes. This protein is composed of two domains of complement inhibitor human factor H (FH complement control protein modules 6 and 7) that bind to S. pyogenes, linked to the Fc region of IgG (FH6-7/Fc). FH6-7/Fc has previously been shown to enhance complement-dependent killing of and facilitate bacterial clearance in animal models of the gram-negative pathogens, Haemophilus influenzae and Neisseria meningitidis. We hypothesized that activation of complement by FH6-7/Fc on the surface of bacteria gram-positive bacteria such as S. pyogenes will enable professional phagocytes to eliminate the pathogen. We found that FH6-7/Fc alleviated S. pyogenes induced sepsis in a transgenic mouse model expressing human FH (S. pyogenes bind FH in a human-specific manner). Furthermore, FH6-7/Fc, which binds to Protein H and select M proteins, displaced FH from the bacterial surface, enhanced alternative pathway activation and reduced bacterial blood burden by opsonophagocytosis in a C3-dependent manner in an ex vivo human whole-blood model. In conclusion, FH-Fc chimeric proteins could serve as adjunctive treatments against multidrug-resistant bacterial infections.
The intracellular pathogen Coxiella (C.) burnetii causes Q fever, a usually self-limiting respiratory infection that becomes chronic and severe in some patients. Innate immune recognition of C. burnetii and its role in the decision between resolution and chronicity is not understood well. However, TLR2 is important for the response to C. burnetii in mice, and genetic polymorphisms in Myd88 have been associated with chronic Q fever in humans. Here, we have employed MyD88-deficient mice in infection models with the attenuated C. burnetii Nine Mile phase II strain (NMII). Myd88−/− macrophages failed to restrict the growth of NMII in vitro, and to upregulate production of the cytokines TNF, IL-6, and IL-10. Following intraperitoneal infection, NMII bacterial burden was significantly higher on day 5 and 20 in organs of Myd88−/− mice. After infection via the natural route by intratracheal injection, a higher bacterial load in the lung and increased dissemination of NMII to other organs was observed in MyD88-deficient mice. While wild-type mice essentially cleared NMII on day 27 after intratracheal infection, it was still readily detectable on day 42 in multiple organs in the absence of MyD88. Despite the elevated bacterial load, Myd88−/− mice had less granulomatous inflammation and expressed significantly lower levels of chemoattractants, inflammatory cytokines, and of several IFNγ-induced genes relevant for control of intracellular pathogens. Together, our results show that MyD88-dependent signaling is essential for early control of C. burnetii replication and to prevent systemic spreading. The continued presence of NMII in the organs of Myd88−/− mice constitutes a new mouse model to study determinants of chronicity and resolution in Q fever.
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