Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection

Abstract

Opsonizing antibody is a critical component of the host protective immune response against many respiratory pathogens. However, the role of antibodies in protection against pulmonary infection with highly virulent strain SchuS4 is unclear, and the mechanism that allows to evade antibody-mediated bacterial clearance is not fully understood. We have now found that depletion of alveolar macrophages reveals an otherwise cryptic protective effect of opsonizing antibody. While antibody opsonization alone failed to confer any survival benefit against SchuS4 lung infection, significant protection was observed when mice were depleted of alveolar macrophages prior to infection. Blood immune signature analyses and bacterial burden measurements indicated that the treatment regimen blocked establishment of productive, systemic infection. In addition, protection was found to be dependent upon neutrophils. The results show for the first time a protective effect of opsonizing antibodies against highly virulent SchuS4 pulmonary infection through depletion of alveolar macrophages, the primary bacterial reservoir, and prevention of systemic dissemination. These findings have important implications for the potential use of therapeutic antibodies against intracellular pathogens that may escape clearance by residing within mucosal macrophages.

SON DNA‐binding protein mediates macrophage autophagy and responses to intracellular infection

“…Francisella tularensis live vaccine strain (LVS) containing pKK214kanGFP [41] was grown in brain–heart infusion with 1% isovitalex (BD biosciences, San Jose, CA, USA) and 15 µg·mL −1 kanamycin at 37 °C. Francisella tularensis ShuS4 was grown overnight in Muller–Hinton broth supplemented with isovitalex, as described elsewhere [42]. Bacteria were washed and resuspended in PBS, then diluted in RPMI + 10% FBS + GM‐CSF and added to transfected AM‐MDMs to a final MOI 10.…”

Host Immunity and Francisella tularensis: A Review of Tularemia in Immunocompromised Patients

“…Furthermore, opsonization of bacteria prior to engulfment by phagocytes improves their intracellular destruction, as Fc receptor mediated phagocytosis was associated with major superoxide production, a rapid NADPH dependent oxidative burst, and a restriction of the phagosomal escape [36]. A recent study showed a protective effect of opsonizing antibodies against highly virulent Francisella tularensis pulmonary infection in mice depleted in alveolar macrophages [37]. According to this information, patients with B cell depletion might present a higher susceptibility to tularemia.…”

Mechanisms Affecting the Acquisition, Persistence and Transmission of Francisella tularensis in Ticks

“…Similarly, R. parkeri , a member of the spotted fever group, was detected in A. americanum tick hemocytes >1 month after infection, providing further evidence that tick hemocytes may not clear all bacterial infections and suggesting that some bacteria may evade tick humoral immune responses by infecting hemocytes [ 125 ]. Parallel comparisons have been made to help explain why F. tularensis infects mammalian macrophages—to evade humoral immune responses (e.g., antibodies) and other host immune responses [ 126 , 127 ]. Clearly, studies are needed to examine how D. variabilis and A. americanum (and potentially other ticks) hemocytes interact with F. tularensis and whether F. tularensis infects tick hemocytes to evade extracellular immune responses.…”