New advances in understanding the host immune response to Pneumocystis

Hoving, J. Claire; Kolls, Jay K.

doi:10.1016/j.mib.2017.10.019

Cited by 30 publications

(23 citation statements)

References 46 publications

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“…In evolutionary terms, P. jirovecii is highly tuned to its human host. This fungus has become so dependent on its intracellular niche that it has shed key metabolic pathways and cannot be cultured in vitro [24]. Despite the homeostatically buffered niche that it occupies, P. jirovecii could conceivably have evolved anticipatory behaviours that predict metabolic or stress responses in the host cell, for example.…”

Section: Evolutionary Trajectories Lifestyles and Anticipatory Behavmentioning

confidence: 99%

Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection

Brown

Gow

Warris

et al. 2019

Trends in Microbiology

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By analogy with Pavlov's dogs, certain pathogens have evolved anticipatory behaviours that exploit specific signals in the human host to prepare themselves against imminent host challenges. This adaptive prediction, a type of history-dependent microbial behaviour, represents a primitive form of microbial memory. For fungal pathogens, adaptive prediction helps them circumvent nutritional immunity, protects them against phagocytic killing, and activates immune evasion strategies. We describe how these anticipatory responses, and the contrasting lifestyles and evolutionary trajectories of fungal pathogens, have influenced the evolution of such adaptive behaviours, and how these behaviours affect host colonisation and infection.

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Section: Evolutionary Trajectories Lifestyles and Anticipatory Behavmentioning

confidence: 99%

Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection

Brown

Gow

Warris

et al. 2019

Trends in Microbiology

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Section: Introductionmentioning

confidence: 99%

“…Host recognition of Pneumocystis and triggering of immune responses is an area of intense research (Hoving and Kolls, 2017; Hoving, 2018; Hauser, 2019). The cyst (ascus) and trofozoite (nuclei) forms exhibit different antigens and both display differing strategies to evade host recognition (Hoving and Kolls, 2017; Hoving, 2018; Hauser, 2019). It is well described that β-glucans present in the thick Pneumocystis cyst wall are recognized by host pattern-recognition receptors such as Dectin-1 and Mincle located in macrophages and by HSPA5 in the airway epithelium thereby activating airway innate immune responses (Krajicek et al, 2009; Ricks et al, 2013; Hoving and Kolls, 2017; Hoving, 2018; Kottom et al, 2018; Hauser, 2019).…”

Section: Introductionmentioning

confidence: 99%

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia

et al. 2019

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Although the role of adaptive immunity in fighting Pneumocystis infection is well known, the role of the innate, airway epithelium, responses remains largely unexplored. The concerted interaction of innate and adaptive responses is essential to successfully eradicate infection. Increased expression of goblet-cell-derived CLCA1 protein plus excess mucus in infant autopsy lungs and in murine models of primary Pneumocystis infection alert of innate immune system immunopathology associated to Pneumocystis infection. Nonetheless, whether blocking mucus-associated innate immune pathways decreases Pneumocystis -related immunopathology is unknown. Furthermore, current treatment of Pneumocystis pneumonia (PcP) relying on anti- Pneumocystis drugs plus steroids is not ideal because removes cellular immune responses against the fungal pathogen. In this study, we used the steroid-induced rat model of PcP to evaluate inflammation and mucus progression, and tested the effect of niflumic acid (NFA), a fenamate-type drug with potent CLCA1 blocker activity, in decreasing Pneumocystis -associated immunopathology. In this model, animals acquire Pneumocystis spontaneously and pneumonia develops owing to the steroids-induced immunodeficiency. Steroids led to decreased animal weight evidencing severe immunosuppression and to significant Pneumocystis -associated pulmonary edema as evidenced by wet-to-dry lung ratios that doubled those of uninfected animals. Inflammatory cuffing infiltrates were noticed first around lung blood vessels followed by bronchi, and both increased progressively. Similarly, airway epithelial and lumen mucus progressively increased. This occurred in parallel to increasing levels of MUC5AC and mCLCA3, the murine homolog of hCLCA1. Administration of NFA caused a significant decrease in total mucus, MUC5AC and mCLCA3 and also, in Pneumocystis -associated inflammation. Most relevant, NFA treatment improved survival at 8 weeks of steroids. Results suggest an important role of innate immune responses in immunopathology of steroid-induced PcP. They warrant evaluation of CLCA1 blockers as adjunctive therapy in this condition and describe a simple model to evaluate therapeutic interventions for steroid resistant mucus, a common condition in patients with chronic lung disease like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis.

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“…Pneumocystis jirovecii is an ascomycetous fungus that causes opportunistic infections, and its life cycle remains unknown because it cannot be consistently cultured [17, 18]. Furthermore, the epidemiology of human PCP is unclear yet [17, 19]. Due to little knowledge about Pneumocystis jirovecii , it is necessary to investigate whether the long term effect of PCP on allografts is due to the infection alone or with chronic inflammatory process and other unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Impact of Pneumocystis jirovecii pneumonia on kidney transplant outcome

et al. 2019

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Backgrounds Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in kidney transplant recipients. While the acute phase toxicity in patients with PCP is well-characterized, there is a lack of data on the effects of PCP on long-term graft outcome. Method This retrospective observational study analyzed 1502 adult patients who underwent kidney transplantation at Seoul National University Hospital between 2000 and 2017. After a propensity score matching was performed, the graft and survival outcomes were compared between PCP-negative and PCP-positive groups. Results A total of 68 patients (4.5%) developed PCP after transplantation. The multivariable Cox analysis showed that positivity for cytomegalovirus and lack of initial oral antibiotic prophylaxis were risk factors of post-transplant PCP. The PCP-positive group had higher hazard ratios of graft failure [adjusted hazard ratio (HR), 3.1 (1.14–8.26); P = 0.027] and mortality [adjusted HR, 11.0 (3.68–32.80); P < 0.001] than the PCP-negative group. However, the PCP event was not related with subsequent development of de novo donor-specific antibodies or pathologic findings, such as T-cell or antibody mediated rejection and interstitial fibrosis and tubular atrophy. Conclusions PCP is a risk factor of long-term graft failure and mortality, irrespective of rejection. Accordingly, appropriate prophylaxis and treatment is needed to avoid adverse transplant outcomes of PCP. Electronic supplementary material The online version of this article (10.1186/s12882-019-1407-x) contains supplementary material, which is available to authorized users.

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New advances in understanding the host immune response to Pneumocystis

Cited by 30 publications

References 46 publications

Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection

Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia

Impact of Pneumocystis jirovecii pneumonia on kidney transplant outcome

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