Impact of Type I Interferons on Susceptibility to Bacterial Pathogens.

Interferons (IFNs) are a broad class of cytokines that have multifaceted roles. Type I IFNs have variable effects when it comes to host susceptibility to bacterial infections, that is, the resulting outcomes can be either protective or deleterious. The mechanisms identified to date have been wide and varied between pathogens. In this review, we discuss recent literature that provides new insights into the mechanisms of how type I IFN signaling exerts its effects on the outcome of infection from the host's point of view.

Trained immunity and host-pathogen interactions.

Infectious diseases are a leading cause of death worldwide with over 8 million fatalities accounted for in 2016. Solicitation of host immune defenses by vaccination is the treatment of choice to prevent these infections. It has long been thought that vaccine immunity was solely mediated by the adaptive immune system. However, over the past decade, numerous studies have shown that innate immune cells can also retain memory of these encounters. This process, called innate immune memory, is mediated by metabolic and epigenetic changes that make cells either hyperresponsive (trained immunity) or hyporesponsive (tolerance) to subsequent challenges. In this review, we discuss the concepts of trained immunity and tolerance in the context of host-pathogen interactions.

Differential Induction of Type I and III Interferons by Staphylococcus aureus.

Staphylococcus aureus is a leading cause of bacterial pneumonia, and we have shown previously that type I interferon (IFN) contributes to the pathogenesis of this disease. In this study, we screened 75 S. aureus strains for their ability to induce type I and III IFN. Both cytokine pathways were differentially stimulated by various S. aureus strains independently of their isolation sites or methicillin resistance profiles. These induction patterns persisted over time, and type I and III IFN generation differentially correlated with tumor necrosis factor alpha production. Investigation of one isolate, strain 126, showed a significant defect in type I IFN induction that persisted over several time points. The lack of induction was not due to differential phagocytosis, subcellular location, or changes in endosomal acidification. A correlation between reduced type I IFN induction levels and decreased autolysis and lysostaphin sensitivity was found between strains. Strain 126 had a decreased rate of autolysis and increased resistance to lysostaphin degradation and host cell-mediated killing. This strain displayed decreased virulence in a murine model of acute pneumonia compared to USA300 (current epidemic strain and commonly used in research) and had reduced capacity to induce multiple cytokines. We observed this isolate to be a vancomycin-intermediate S. aureus (VISA) strain, and reduced Ifnb was observed with a defined mutation in walK that induces a VISA phenotype. Overall, this study demonstrates the heterogeneity of IFN induction by S. aureus and uncovered an interesting property of a VISA strain in its inability to induce type I IFN production.

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice.

Acinetobacter baumannii (A. baumannii) is an extremely versatile multidrug-resistant pathogen with a very high mortality rate; therefore, it has become crucial to understand the host response during its infection. Given the importance of mice for modeling infection and their role in preclinical drug development, equal emphasis should be placed on the use of both sexes. Through our studies using a murine model of acute pneumonia with A. baumannii, we observed that female mice were more susceptible to infection. Likewise, treatment of male mice with estradiol increased their susceptibility to infection. Analysis of the airway compartment revealed enhanced inflammation and reduced neutrophil and alveolar macrophage numbers compared with male mice. Depletion of either neutrophils or alveolar macrophages was important for bacterial clearance; however, depletion of alveolar macrophages further exacerbated female susceptibility because of severe alterations in metabolic homeostasis. Our data highlight the importance of using both sexes when assessing host immune pathways.

A novel blood-feeding detoxification pathway in Nippostrongylus brasiliensis L3 reveals a potential checkpoint for arresting hookworm development.

As part of on-going efforts to control hookworm infection, the "human hookworm vaccine initiative" has recognised blood feeding as a feasible therapeutic target for inducing immunity against hookworm infection. To this end, molecular approaches have been used to identify candidate targets, such as Necator americanus (Na) haemoglobinase aspartic protease-1 (APR-1), with immunogenicity profiled in canine and hamster models. We sought to accelerate the immune analysis of these identified therapeutic targets by developing an appropriate mouse model. Here we demonstrate that Nippostrongylus brasiliensis (Nb), a phylogenetically distant strongylid nematode of rodents, begins blood feeding early in its development and that immunisation with Na-APR-1 can block its growth and completion of its life cycle. Furthermore, we identify a new haem detoxification pathway in Nb required for blood feeding that can be blocked by drugs of the quinolone family, reducing both infection burden and the associated anaemia in rodents. Collectively, our findings show that haem metabolism has potential as a checkpoint for interrupting hookworm development in early stages of the hookworm life cycle and that the Nippostrongylus brasiliensis rodent model is relevant for identifying novel therapeutic targets against human hookworm.