Human Immune Response Varies by the Degree of Relative Cryptococcal Antigen Shedding

Boulware, David R.; Hohenberg, Maximilian von; Rolfes, Melissa A.; Bahr, Nathan C; Rhein, Joshua; Akampurira, Andrew; Williams, Darlisha A; Taseera, Kabanda; Schutz, Charlotte; McDonald, Tami; Muzoora, Conrad; Meintjes, Graeme; Meya, David B.; Nielsen, Kirsten; Hullsiek, Katherine Huppler

doi:10.1093/ofid/ofv194

Cited by 19 publications

(23 citation statements)

References 24 publications

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“…However, without this specific CD4 T-cell response before CM treatment, patients had a markedly dysregulated immune upregulation of MIP-1-a and MCP-1 post-ART, leading to over-inflammation and IRIS [22]. This finding agrees with that of another study showing increased MCP-1 and MIP-1-a CNS expression at baseline associated with IRIS post-treatment, leading to the hypothesis of CD8 T-cell and myeloid trafficking, in response to these chemokines, playing a major role in the overreactive immune response and excessive inflammation [13].…”

Section: Iris Biomarkerssupporting

confidence: 89%

“…Phagocytic macrophages are a primary line of defence against cryptococci; however, they can survive and replicate within the phagolysosomes of alternatively activated macrophages [14], contributing to fungal persistence. Further, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colonystimulating factor (GM-CSF), related to macrophage functionality and M1 polarization, are decreased pre-therapy and correlated to less effective fungal clearance [11,13] through a lack of M1 macrophages engulfing and degrading cryptococci [2]. In murine models, it has been shown that the fungus capsule destabilizes the immune response, causing a Th2mediated response and leading to increased mortality [15].…”

Section: Pathophysiology and Manifestationmentioning

confidence: 99%

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Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV‐Infected Individuals

Balasko

Keynan

2018

HIV Medicine

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Objectives The aim of this work was to review current treatment options and propose alternatives for immune reconstitution inflammatory syndrome (IRIS) in HIV‐infected individuals with cryptococcal meningitis (CM) (termed ‘HIV‐CM IRIS’). As a consequence of the immunocompromised state of these individuals, the initial immune response to CM is predominantly type 2 T helper (Th2) /Th17 rather than Th1, leading to inefficient fungal clearance at the time of antiretroviral initiation, and a subsequent overexaggeration of the Th1 response and life‐threatening IRIS development. Methods An article‐based and clinical trial‐based search was conducted to investigate HIV‐CM IRIS pathophysiology and current treatment practices. Results Guidelines for CM treatment, based on the Cryptococcal Optimal Antiretroviral Timing (COAT) trial, recommend delayed antiretroviral therapy (ART) following antifungal treatment. The approach aims to decrease fungal burden and allow immune balance restoration prior to ART initiation. If the initial immune balance is not restored, the fungal burden is not sufficiently reduced and there is a risk of developing IRIS post‐ART, highlighted by a Th1 immune overcompensation, leading to increased mortality. The mainstay treatment for Th1‐biased IRIS is corticosteroids; however, this treatment has been shown to correlate with increased mortality and significant associated adverse events. We emphasize targeting a more specific Th1 mechanism via the tumour necrosis factor (TNF)‐α cytokine antagonist thalidomide, as it is the only TNF‐α antagonist currently approved for use in infectious disease settings and has been shown to decrease Th1 overreaction, restoring immune balance in HIV‐CM IRIS. Conclusions Although the side effects and limitations of thalidomide must be considered, it is currently being successfully used in infectious disease settings and warrants mainstream application as a therapeutic option for treatment of IRIS in HIV‐infected patients with CM.

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Section: Iris Biomarkerssupporting

confidence: 89%

Section: Pathophysiology and Manifestationmentioning

confidence: 99%

Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV‐Infected Individuals

Balasko

Keynan

2018

HIV Medicine

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“…Previous studies showed that pathogen-specific characteristics, such as the genotype or the degree of antigen shedding, influence immune responses to C. neoformans and the clinical outcome of patients (5,(7)(8)(9). Multilocus sequence typing (MLST) of 7 genetic loci has previously been used to identify genetically similar strains (5)(6)(7)(8)(9)(10). For example, studies of clinical isolates in both Uganda and Brazil showed higher patient mortality associated with sequence type 93 (ST93) strains (5,10).…”

mentioning

confidence: 99%

The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence

et al. 2019

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Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet the Cryptococcus factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with the clinical outcome, but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIVinfected cryptococcal meningitis patients infected with Cryptococcus neoformans strains with the same multilocus sequence type (MLST). Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome was not associated with the patient CD4 count. Patient mortality was associated with higher cryptococcal antigen levels, the cerebrospinal fluid (CSF) fungal burden by quantitative culture, and low CSF fungal clearance. The virulence of a subset of clinical strains with the same sequence type was analyzed using a mouse inhalation model of cryptococcosis. We showed a strong association between human and mouse mortality rates, demonstrating that the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply in vivo, demonstrated by a high fungal burden in lung and brain tissues, was associated with mouse mortality. Mouse survival time was not associated with single C. neoformans virulence factors in vitro or in vivo; rather, a trend in survival time correlated with a suite of traits. These observations show that MLST-derived genotype similarities between C. neoformans strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that in vitro assays do not fully reproduce in vivo conditions that influence C. neoformans virulence.

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“…Institutional Review Board approvals were obtained from each participating site. A total of 106 patients that had culture-positive CSF for Cryptococcus and from which isolates were sequenced for genotypic analyses (5, 8) were included in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Cryptococcus clinical isolates were colony-purified from the cerebrospinal fluid (CSF) specimens from patients enrolled in the COAT trial and multi-locus sequence type (MSLT) was determined previously (5, 8). The strains used in this study are listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Closely related Cryptococcus neoformans strains possess differential virulence both in humans and the mouse inhalation model

Mukaremera

McDonald

Nielsen

et al. 2019

Preprint

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24Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet Cryptococcus 25 factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the 26 strain genotype and degree of antigen shedding, are associated with clinical outcome but the 27 underlying biology remains elusive. In this study, we examined factors determining disease 28 outcome in HIV-infected cryptococcal meningitis patients infected with C. neoformans strains 29 with the same multi-locus sequence type. Both patient mortality and survival were observed 30 during infections with the same sequence type. Disease outcome did not correlate with 31 underlying patient immune deficiencies. Patient mortality was associated with higher antigen 32 levels, fungal burden in the CSF, and low CSF fungal clearance. Virulence of a subset of clinical 33 strains with the same sequence type were analyzed using the mouse inhalation model of 34 cryptococcosis. We showed a strong correlation between human and mouse mortality rates, 35 demonstrating the mouse inhalation model recapitulates human infection. Similar to human 36 infection, the ability to multiply in vivo, demonstrated by high fungal burden in the lung and 37 brain tissues, was associated with mouse mortality. Mortality rate was not associated with single 38 C. neoformans virulence factors in vitro or in vivo; rather, a trend in mortality rate correlated 39 with a suite of traits. These observations show that genotype similarities between C. neoformans 40 strains do not necessarily translate into similar virulence either in the mouse model or in human 41 patients. In addition, our results show that in vitro assays do not fully reproduce in vivo 42 conditions that influence C. neoformans virulence. 44Cryptococcus neoformans is a fungal pathogen that causes disease mainly in 45 immunocompromised patients such as individuals living with HIV/AIDS or receiving organ 46 transplants. The availability of antiretroviral therapy has reduced AIDS-related mortality, 47 however deaths due to cryptococcal meningitis (CM) have plateaued with C. neoformans still 48 causing 15 % of all AIDS-related deaths globally (1, 2). Mortality rates due to Cryptococcus 49 infection varies by region from 70% in low-income countries to 20-40% of all infected patients 50 in high-income countries (2). Although differences in mortality rates between high-and low-51 income countries can be linked to sub-optimal antifungal treatments in low-income countries (3), 52 variations in mortality rates between patient groups receiving similar treatments and residing in 53 the same region of the world are observed (1,(4)(5)(6). Mortality is a measure influenced by many 54 intrinsic host and pathogen factors (as well as host-pathogen interaction factors). Thus, we need 55 better proxies to understand C. neoformans pathogenesis in patients and identify factors 56 determining clinical outcome. 57Although C. neoformans pathogenesis in the mouse model of cryptococcosis has been 58 extensively studied, the...

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Human Immune Response Varies by the Degree of Relative Cryptococcal Antigen Shedding

Cited by 19 publications

References 24 publications

Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV‐Infected Individuals

Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV‐Infected Individuals

The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence

Closely related Cryptococcus neoformans strains possess differential virulence both in humans and the mouse inhalation model

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