Monocyte/macrophage inflammatory response pathways to combat Francisella infection: possible therapeutic targets?

Abstract

Francisella tularensis can bypass and suppress host immune responses, even to the point of manipulating immune cell phenotypes and intercellular inflammatory networks. Strengthening these responses such that immune cells more readily identify and destroy the bacteria is likely to become a viable (and perhaps necessary) strategy for combating infections with Francisella, especially given the likelihood of antibiotic resistance in the foreseeable future. Monocytes and macrophages offer a niche wherein Francisella can invade and replicate, resulting in substantially higher bacterial load that can overcome the host. As such, understanding their responses to Francisella may uncover potential avenues of therapy that could promote a lowering of bacterial burden and clearance of infection. These response pathways include Toll-like Receptor 2 (TLR2), the caspase-1 inflammasome, Interferons, NADPH oxidase, Phosphatidylinositide 3-kinase (PI3K), and the Ras pathway. In this review we summarize the literature pertaining to the roles of these pathways during Francisella infection, with an emphasis on monocyte/macrophage responses. The therapeutic targeting of one or more such pathways may ultimately become a valuable tool for the treatment of tularemia, and several possibilities are discussed.

Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases

“…Since then, their regulatory role in additional hematopoietic cell types, including platelets and mast cells, has been described (22,23). As a wide range of leukocytes, including bone marrow-derived phagocytes and granulocytes, play a critical role during the initial primary immune response to F. tularensis (9,12,37), this study suggests the Sts proteins regulate immunological responses in a broader population of cells than previously appreciated. The enhanced restriction of F. tularensis in Sts Ϫ/Ϫ bone marrow-derived monocytes relative to wild-type bone marrow-derived monocytes following ex vivo infection supports this hypothesis.…”

“…In recent years, the intracellular life cycle of Francisella, bacterial pathogenicity mechanisms, and host inflammatory responses to Francisella infection have been the subject of intense study (10)(11)(12). After phagocytosis into host cells following interactions with either the complement receptor CR3, mannose receptors, class A scavenger receptors, or Fc␥ receptors, Francisella enters into a vacuolar compartment known as the Francisella-containing phagosome (FCP) (13).…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…Schu S4, the most pathogenic strain of Francisella , can actively dampen and subvert the inflammatory response [96], reduce the expression of autophagy-related genes, and compromise relevant signaling pathways in human hosts. In particular, F. tularensis Schu S4, significantly downregulates the expression of autophagy related genes such as BEC1, ATG5, ATG12, ATG16L2, ATG7, ATG4A , and PIK3R1 but increases expression of IFNG and IFNB1 [117,118].…”

Francisella tularensisas a potential agent of bioterrorism?

“…The activation of macrophages may be obtained in several ways, including using antimicrobial peptides, cytokines such as IFN-g and TNF-a, cytokines production activators (e.g. galantamine), cystatins or Toll-like receptor (TLR)-signaling pathway activators (especially TLR4 agonists) [18,[27][28][29]. It is certain that these lines of research will lead to the discovery of new defense strategies against bioterrorism agents.…”