Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome

Boulware, David R.; Bonham, Shulamith C.; Meya, David B.; Wiesner, Darin L.; Park, Gregory S.; Kambugu, Andrew; Janoff, Edward N.; Bohjanen, Paul R.

doi:10.1086/655785

Cited by 178 publications

(221 citation statements)

References 45 publications

Supporting

Mentioning

206

Contrasting

Unclassified

Order By: Relevance

“…Notably, in that study, median CD4 counts were higher than those in patients who did not develop IRIS (299). Unlike in HIV-positive patients, neither initial CSF cryptococcal antigen (CRAG) titers nor CSF leukocyte counts and protein levels differed from those in patients who did not develop IRIS (299,300). However, since patients with C. gattii who subsequently developed IRIS all presented with cryptococcomas in the brain, CSF parameters likely did not reflect the fungal load (or immune response) in this site.…”

Section: Immune Reconstitution Inflammatory Syndromementioning

confidence: 57%

Cryptococcus gattii Infections

2014

View full text Add to dashboard Cite

SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

show abstract

Section: Immune Reconstitution Inflammatory Syndromementioning

confidence: 57%

Cryptococcus gattii Infections

2014

View full text Add to dashboard Cite

show abstract

“…Clinical evidence increasingly suggests that the host inflammatory response, rather than pathogen burden, may lead to the development of pathology, neuronal injury, and deteriorating status, especially in IRIS and PIIRS patients (28,30,32,33,(36)(37)(38)(39)(40). Thus, our next goal was to evaluate CNS pathology during the progression of C. neoformans infection and to determine a possible link to the accumulation of a cellular inflammatory response within the CNS.…”

Section: Resultsmentioning

confidence: 99%

“…T cell inflammatory response in the CNS during cryptococcal meningoencephalitis is highly Th1 polarized, and nearly all CD4 ؉ and CD8 ؉ T cells produce IFN-␥. The subsets of patients with paradoxical inflammatory responses to cryptococcal infection (IRIS and PIIRS) display dominant Th1 T cell polarization with elevated levels of IFN-␥ in the serum and CSF (32,33,(36)(37)(38)(39)(40). Thus, we sought to determine whether murine brain-infiltrating T cells would mimic this phenotype by analyzing T cell cytokine production and expression of polarizing Th-associated transcription factors in the C. neoformans-infected CNS.…”

Section: Resultsmentioning

confidence: 99%

CD4 ⁺ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

Neal

Xing

et al. 2017

mBio

100

View full text Add to dashboard Cite

Cryptococcus neoformans is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4 ϩ T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIVpositive (HIVϩ) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45 hi leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-␥)-producing CD4 ϩ T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4 ϩ cells significantly impaired IFN-␥ production, CD8 ϩ T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4 ϩ T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections.IMPORTANCE CNS infection with the fungal pathogen Cryptococcus neoformans often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIVϩ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with antiinflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and

show abstract

“…It is hypothesized that the increase in mortality is related to immune reconstitution inflammatory syndrome (IRIS) and that the impact is greater earlier in the course of treatment, when the patient has not yet begun to recover from the original intracerebral insult and has limited reserves. In keeping with this theory, Boulware et al noted that the increased mortality was especially pronounced in patients with a baseline CSF white cell count <5 cells/mm 3 [176•], an established risk factor for IRIS [179,180].…”

Section: Antifungal Therapy-a Model For Clinical Researchmentioning

confidence: 99%

A Model CNS Fungal Infection: Cryptococcal Meningitis

Beardsley

Thanh

Day

2015

Curr Clin Micro Rpt

View full text Add to dashboard Cite

Cryptococcus spp. are considered 'model yeasts', and the reasons for that are the topic of this review. Several perspectives will be discussed, starting with their characterization and emergence as human pathogens before moving onto their adaptations and the scientific response. The section on characterization illustrates the progress of knowledge and technology over the 120 years since Cryptococcus was first identified, whilst the section on emergence sees this applied to describe the expansion of the host population and environmental niche. The ongoing outbreak in the Pacific northwest of North America is discussed, including some of its drivers. The section on adaptation highlights some insights into how eukaryotes adapt both to their environment and within hosts, and the final section covers the scientific response to this threat in terms of treatment and prevention. The review highlights both clinical and laboratory features of particular interest and places them into the wider context of this still emerging threat.Keywords Cryptococcus . Emergence . Characterization . Adaptation . Environmental niche . ResearchCryptococcus spp. are considered 'model yeasts' by many researchers-the reasons for that are the topic of this review. Several perspectives will be discussed, starting with their characterization and emergence as human pathogens before moving onto their adaptations and the scientific response. The section on characterization illustrates the progress of knowledge and technology over the 120 years since Cryptococcus was first identified, whilst the section on emergence sees this applied to describe the expansion of the host population and environmental niche. The ongoing outbreak in the Pacific northwest of North America is discussed, including some of its drivers. The section on adaptation highlights some insights into how eukaryotes adapt both to their environment and within hosts, and the final section covers the scientific response to this threat in terms of treatment and prevention. It is beyond the scope of the review to cover every aspect of cryptococcosis, and the intention is just to summarize current knowledge of key topics and provide a starting point for further reading about this fascinating, complicated and important human pathogen.

show abstract

Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome

Cited by 178 publications

References 45 publications

Cryptococcus gattii Infections

Cryptococcus gattii Infections

CD4 ⁺ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

A Model CNS Fungal Infection: Cryptococcal Meningitis

Contact Info

Product

Resources

About

Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome

Cited by 178 publications

References 45 publications

Cryptococcus gattii Infections

Cryptococcus gattii Infections

CD4 + T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

A Model CNS Fungal Infection: Cryptococcal Meningitis

Contact Info

Product

Resources

About

CD4 ⁺ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis