Modulating Host Signaling Pathways to Promote Resistance to Infection by Candida albicans

Carpino, Nick; Naseem, Saadia; Frank, David; Konopka, James B.

doi:10.3389/fcimb.2017.00481

Cited by 25 publications

(21 citation statements)

References 88 publications

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“…The innate host defense to infection depends on the recruitment of inflammatory leukocytes; however, the cellular damage produced by a hyperinflammatory response can worsen fungal pathology ( 40 – 42 ). The inflammatory environment of infected kidneys was evaluated by measuring the levels of chemokines in uninfected mice or mice infected with C. albicans for 48 or 72 hpi.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection

Stawowczyk

Naseem

Montoya

et al. 2018

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A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to C. albicans infection. IFN-β treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-β has deleterious effects during infection.

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Section: Resultsmentioning

confidence: 99%

Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection

Stawowczyk

Naseem

Montoya

et al. 2018

mBio

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“…Combination therapy that pairs the use of traditional antibiotics with agents to enhance beneficial host immune responses is considered an important therapeutic goal for the treatment of intractable infections and of those for which antibiotic resistance is a looming concern ( 11 , 12 ). Interestingly, genetic inactivation of the Sts proteins dramatically improves host survival following lethal doses of intravenous C. albicans , suggesting that they are possible targets to enhance host antifungal immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Fungal cell wall constituents are recognized by cell-surface Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), promoting the activation of cellular antimicrobial effector pathways ( 10 ). However, excessive inflammatory responses that occur in the context of fungal infections can also be counterproductive and lead to detrimental collateral tissue damage ( 11 , 12 ). For example, in a mouse model of systemic candidiasis, progressive sepsis caused by a vigorous inflammatory response has been identified as the cause of death ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

Frank

Naseem

Russo

et al. 2018

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Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis.

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“…First, unlike obligate pathogens with no commensal relationship with humans, this tolerance represents an additional hurdle toward establishment of effective and protective immunological memory. Second, much of the clinical manifestations of Candida -related infections are more due to host-derived immunopathology than to pathogen-derived host damage ( 116 , 117 ). For instance, mice lacking the chemokine receptor Ccr1, which is critical for neutrophil recruitment, display improved renal function during invasive candidiasis ( 118 ) and administration of Ccr1 antagonists reduces renal tissue injury and improves survival in mice challenged with systemic candidiasis ( 119 ).…”

Section: Common Challenges Faced So Farmentioning

confidence: 99%

The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future

2018

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Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40–50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of “trained immunity” and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens.

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Modulating Host Signaling Pathways to Promote Resistance to Infection by Candida albicans

Cited by 25 publications

References 88 publications

Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection

Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection

Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future

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