Virulence Factors Identified by Cryptococcus neoformans Mutant Screen Differentially Modulate Lung Immune Responses and Brain Dissemination

He, Xiumiao; Lyons, Daniel M.; Toffaletti, Dena L.; Wang, Fuyuan; Qiu, Yafeng; Davis, Michael J.; Meister, Daniel; Dayrit, Jeremy K.; Lee, Anthony; Osterholzer, John J.; Perfect, John R.; Olszewski, Michal A.

doi:10.1016/j.ajpath.2012.06.012

Cited by 25 publications

(28 citation statements)

References 53 publications

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“…These factors, such as urease (15, 26, 50), phospholipase (46, 51), and laccase (27) promote the development of non-protective Th2 immunity and subsequent M2 polarization and confer a fungal growth advantage late during the infection. It is also in contrast with other factors, such as PIK1 , RUB1, ENA1 (28), and VAD1 (52), which confer growth advantages during both the innate and adaptive phase of the immune response but nevertheless predominantly modulate the cytokine environment during the efferent phase of the immune response in C. neoformans -infected lungs. In contrast, Ssa1 directly modulates macrophage- C. neoformans interactions only during the innate phase, with little to no effect on the development of adaptive immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Another group of virulence-associated genes including a phosphatidylinositol 4-kinase ( PIK1 ), a ubiquitin-like protein ( RUB1 ), and a cation ATPase transporter ( ENA1 ), promote cryptococcal survival in the host’s tissues and thus contribute to early fungal growth. However, the overall level of virulence conferred by each of these factors correlates with their effects on the adaptive immune response polarization and subsequent macrophage polarization status during the efferent phase of host response (28). …”

Section: Introductionmentioning

confidence: 99%

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Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

Eastman

Qiu

et al. 2015

The Journal of Immunology

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Numerous virulence factors expressed by C. neoformans (C. neo) modulate host defenses by promoting non-protective Th2-biased adaptive immune responses. Prior studies demonstrate that the HSP70 homologue, Ssa1, significantly contributes to serotype-D C. neo virulence through the induction of laccase, a Th2-skewing and CNS-tropic factor. In the current study, we sought to determine whether Ssa1 modulates host defenses in mice infected with a highly virulent serotype A (serA) strain of C. neo (H99). To investigate this, we assessed pulmonary fungal growth, CNS dissemination, and survival in mice infected with either H99, an SSA1-deleted H99 strain (Δssa1), and a complement strain with restored SSA1 expression (Δssa1::SSA1). Mice infected with the Δssa1 strain displayed substantial reductions in lung fungal burden during the innate phase (days 3 and 7) of the host response whereas less pronounced reductions were observed during the adaptive phase (day 14) and mouse survival increased only by 5 days. Surprisingly, laccase activity assays revealed that Δssa1 was not laccase-deficient, demonstrating that H99 does not require Ssa1 for laccase expression, which explains the CNS tropism we still observed in the Ssa1-deficient strain. Lastly, our immunophenotyping studies showed that Ssa1 directly promotes early M2 skewing of lung mononuclear phagocytes during the innate, but not the adaptive phase of the immune response. We conclude that Ssa1’s virulence mechanism in H99 is distinct and laccase-independent. Ssa1 directly interferes with early macrophage polarization, limiting innate control of C. neo, but ultimately has no effect on cryptococcal control by adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

Eastman

Qiu

et al. 2015

The Journal of Immunology

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“…8b). Interestingly, infection routes determine the virulence phenotype of ctr1Dctr4D, implying that entry rather than replication of C. neoformans in the brain is critical for fungal virulence in the mouse model 44,45 . Because the ctr1Dctr4D strain remains virulent in the intracerebral infection model, we speculate that there are other Cu uptake machineries in C. neoformans that are active in Cu transport during the formation of meningoencephalitis.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

et al. 2014

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“…However, subsequently, the wt strain triggers additional IFN-␥ production in the lungs by day 7 but is accompanied by an increase in IL-4, while the ⌬vad1 strain does not induce IL-4, thus maintaining a low IL-4/IFN-␥ ratio (Fig. 5C), known to be beneficial for cryptococcal clearance (19,43). Increased production of inflammatory cytokines/chemokines such as KC and retained production of TNF-␣ likely contributed to effective innate clearance of the mutant strain as suggested by previous studies (44,45).…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformans Growth and Protection from Innate Immunity Are Dependent on Expression of a Virulence-Associated DEAD-Box Protein, Vad1

2013

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The fungus Cryptococcus neoformans has emerged as a major cause of meningoencephalitis worldwide. Host response to the fungus involves both innate and adaptive immunity, but fungal genes that modulate these processes are poorly understood. Previous studies demonstrated attenuated virulence of a mutant of a virulence-associated DEAD-box protein (VAD1) in mice, despite normal growth at host temperatures, suggesting modulation of the immune response. In the present study, the ⌬vad1 mutant demonstrated progressive clearance from lung and was unable to induce pathological lesions or to cause extrapulmonary disease, despite retaining its ability to grow in mouse serum and a J774.

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Virulence Factors Identified by Cryptococcus neoformans Mutant Screen Differentially Modulate Lung Immune Responses and Brain Dissemination

Cited by 25 publications

References 53 publications

Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Cryptococcus neoformans Growth and Protection from Innate Immunity Are Dependent on Expression of a Virulence-Associated DEAD-Box Protein, Vad1

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