Humoral and cell‐mediated immunity to the intracellular pathogen <i>Francisella tularensis</i>

Kirimanjeswara, Girish S.; Olmos, Sofı́a; Bakshi, Chandra Shekhar; Metzger, Dennis W.

doi:10.1111/j.1600-065x.2008.00689.x

Cited by 107 publications

(117 citation statements)

References 94 publications

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“…Cell-mediated immunity is generally considered to be essential for immunity against intracellular pathogens, and humoral immunity is thought to have more of an ancillary role. However, significant evidence in the literature indicates an important role of antibodies against F. tularensis LVS infection (13)(14)(15)(16)(17). Moreover, studies from our laboratory have recently reported a synergistic effect of humoral and cellular immune responses in providing sterilizing immunity against respiratory LVS infection (13).…”

Section: F Tularensis Lvs Infection Causes Significant Tissue Patholmentioning

confidence: 94%

Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection

et al. 2013

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Francisella tularensis, the causative agent of tularemia, is most deadly in the pneumonic form; therefore, mucosal immunity is an important first line of defense against this pathogen. We have now evaluated the lethality of primary F. tularensis live vaccine strain (LVS) pulmonary infection in mice that are defective in IgA (IgA ؊/؊ mice), the predominant mucosal Ig isotype. The results showed that IgA ؊/؊ mice were more susceptible than IgA ؉/؉ mice to intranasal F. tularensis LVS infection, despite developing higher levels of LVS-specific total, IgG, and IgM antibodies in the bronchoalveolar lavage specimens following infection. In addition, the absence of IgA resulted in a significant increase in bacterial loads and reduced survival. Interestingly, IgA

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Section: F Tularensis Lvs Infection Causes Significant Tissue Patholmentioning

confidence: 94%

Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection

et al. 2013

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“…This is evident in murine models of tularemia, where robust proinflammatory responses are not observed during the first 48 to 72 h of infection (20)(21)(22)(23)(24). F. tularensis also dampens host-programmed cell death responses during infection (20,(25)(26)(27)(28)(29)(30)(31). Death of F. tularensis-infected cells occurs via two primary mechanisms: caspase-1-mediated pyroptosis and caspase-3-mediated apoptosis (25,32).…”

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confidence: 93%

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

et al. 2014

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Francisella tularensis is a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of the F. tularensis live vaccine strain (LVS) and demonstrated that a ⌬tolC mutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required for F. tularensis to preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ⌬tolC mutant. These findings support a model wherein the immunomodulatory capacity of F. tularensis relies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ⌬tolC LVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ⌬tolC mutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection by F. tularensis and highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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“…IFN-␥-stimulated alveolar macrophages also secrete tumor necrosis factor alpha (TNF-␣); while it is not necessary for these cells to control F. tularensis LVS in vitro, it is required for protection in vivo (16). This suggests the involvement of other cell populations, possibly neutrophils, which are recruited to the lung within 3 days of F. tularensis infection (4,13).…”

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confidence: 99%

“…Macrophages significantly contribute to in vitro bacterial killing if they are stimulated with interferon gamma (IFN-␥) (2,(11)(12)(13). Correspondingly, IFN-␥ is known to be required for protection in vivo (14).…”

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confidence: 99%

Protective Role for Macrophages in Respiratory Francisella tularensis Infection

et al. 2017

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Francisella tularensis causes lethal pneumonia following infection of the lungs by targeting macrophages for intracellular replication; however, macrophages stimulated with interferon gamma (IFN-␥) can resist infection in vitro. We therefore hypothesized that the protective effect of IFN-␥ against F. tularensis in vivo requires macrophages receptive to stimulation. We found that the lethality of pulmonary F. tularensis LVS infection was exacerbated under conditions of alveolar macrophage depletion and in mice with a macrophage-specific defect in IFN-␥ signaling (termed mice with macrophages insensitive to IFN-␥ [MIIG mice]). We previously found that treatment with exogenous interleukin 12 (IL-12) protects against F. tularensis infection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render wild-type mice highly sensitive to respiratory F. tularensis infection, and depletion beginning at 3 days postinfection led to more pronounced sensitivity than depletion beginning prior to infection. Furthermore, IL-12-mediated protection required NADPH oxidase activity. These results indicate that lung macrophages serve a critical protective role in respiratory F. tularensis LVS infection. Macrophages require IFN-␥ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.KEYWORDS interferons, lung defense, lung infection, macrophages, neutrophils, tularemia T he tier 1 biothreat Francisella tularensis is a Gram-negative bacterium that is capable of replicating within phagocytes (1-3). In respiratory infection, alveolar macrophages have been reported to be the primary host cell for replication (4-6). It has been suggested that alveolar phagocytes are therefore detrimental to the host during respiratory infection, and a 2005 study reported that depletion of alveolar phagocytes following high challenge doses of LVS resulted in a modestly delayed time to death (7). The course of disease is characterized by a delayed immune response, followed by systemic dissemination and sepsis (8-10). Consequently, the prevailing opinion is that F. tularensis evades destruction by innate immunity and subverts myeloid cells, particularly macrophages, for its own benefit.Despite the proficiency of F. tularensis in subverting and exploiting host immunity, it is possible to stimulate innate immunity to successfully counter F. tularensis infection. Macrophages significantly contribute to in vitro bacterial killing if they are stimulated with interferon gamma (IFN-␥) (2,(11)(12)(13). Correspondingly, IFN-␥ is known to be required for protection in vivo (14). Treatment with exogenous interleukin 12 (IL-12) has been shown to protect mice, and mice lacking either the IL-12p35 or IL-12p40 subunit

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Humoral and cell‐mediated immunity to the intracellular pathogen Francisella tularensis

Cited by 107 publications

References 94 publications

Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection

Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

Protective Role for Macrophages in Respiratory Francisella tularensis Infection

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