The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

Abstract

P neumocystis species are opportunistic fungal pathogens that cause severe pneumonia in immunocompromised hosts, including AIDS patients. Clearance of Pneumocystis organisms is dependent on effective CD4ϩ T and B cell and macrophage responses (1-4). Failure to clear Pneumocystis organisms leads to severe alveolar damage due to the exaggerated inflammatory immune response (5). In spite of a reduced incidence of Pneumocystis pneumonia (PcP) in HIV-infected individuals due to improved antiviral therapies, the mortality rate for patients with PcP has not improved with the implementation of highly active antiretroviral therapy (HAART) (6). Additional studies are required to inform novel approaches to reduce morbidity and mortality due to Pneumocystis pneumonia.Outbreaks of PcP were first described in malnourished or premature infants in orphanages following the Second World War (7). Evidence suggests that immunocompetent individuals of all ages are capable of mounting protective immune responses to Pneumocystis jirovecii that prevent progression to pneumonia. Most children encounter this opportunistic fungus at a young age, as indicated by the presence of specific antibodies in the sera of 85% of individuals by the age of 3 years (8). Previous work from our lab has shown that the neonatal mouse immune response to Pneumocystis is delayed, due in part to an anti-inflammatory lung environment (9-12). The neonatal lung environment is characterized by anti-inflammatory mediators, including transforming growth factor ␤1 (TGF-␤1) and interleukin 10 (IL-10), and immature immune cells (9-12). Neonatal alveolar macrophages and T cells adoptively transferred to an adult lung environment are competent at resolving Pneumocystis murina pneumonia in mice (9, 12). In addition, neonatal alveolar macrophages are deficient in NF-B translocation following stimulation with Pneumocystis organisms (9). Neonatal alveolar CD11c ϩ cells demonstrate delayed trafficking to the draining lymph nodes (11). Together, these data indicate that both the neonatal lung environment and intrinsic immune cell deficits contribute to the delayed clearance of P. murina in neonatal mice.Pneumocystis species have a biphasic life cycle. Trophic forms are proposed to represent the asexual stage of the life cycle, whereas cysts are the ascus-like sexual stage (13). Trophic forms are single-nucleated organisms that are typically found in clusters surrounded by a biofilm-like substance consisting of a conglomeration of DNA, ␤-glucan, and other sugars (14). Cysts are ascuslike structures that consist of multiple nuclei surrounded by a fungal cell wall. ␤-1,3-Glucan and ␤-1,6-glucan serve as the structural components of the cyst wall (15, 16). Trophic forms do not express ␤-glucan (15). Both stages express surface glycoproteins and mannoproteins, which may serve as pathogen-associated molecular patterns (PAMPs) that could interact with receptors on phagocytic cells (17)(18)(19). Neither life form expresses chitin or ␣-glucans (20).Dendritic cells are the principal ant...

The Interaction of Pneumocystis with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense against Infection

“…The counter-regulatory generation of anti-inflammatory IL-1Ra release mediated by Mincle receptors and not previously reported during PCP, may, on one hand represent a means to limit lung tissue damage during infection, but may also represent an important mechanism through which Pneumocystis species persist in the lung environment by dampening the host responses to infection. Indeed, recently Garvy et al demonstrated that the trophic life cycle forms of Pm suppress β-glucan induced proinflammatory cytokine responses, associated with the β-glucan rich Pm cysts wall (68). It will be interesting in future studies to determine if Pneumocystis trophic forms might actively modulate anti-inflammatory immune cytokines such as IL-1Ra as a mechanism to persist and propagate in the host.…”

New advances in understanding the host immune response to Pneumocystis

“…These cells play a crucial role in recognising, binding and initiating the CD4 + T cell host response to Pneumocystis . While the type of cell that primes a T-cell in response to Pneumocystis is important, a recent study has also highlighted that the form of organism affects the host response to infection [31]. In contrast to the ascus, the trophic form lacks a cell wall and therefore innate cells respond poorly with reduced CD4+ T-cell recruitment and IFNγ production [32].…”

A critical role for CARD9 in pneumocystis pneumonia host defence

“…The Pneumocystis inoculum used was purified by differential filtration as we reported to remove host related debris (Kottom et al, 2017). We utilised intratracheal instillation to insure that each mouse received comparable organism inoculation load, and such intratracheal instillation has been used to study host responses to Pneumocystis (Evans, Bryant, & Garvy, 2016; Hoy et al, 2020; Rapaka et al, 2010). For the immunocompetent infection model, mice were sacrificed at 20 days after infection (Kottom et al, 2018).…”