Opportunistic fungal infection is a common cause of serious morbidity and mortality in immunocompromised individuals, including AIDS patients, cancer patients under chemotherapy, and immunosuppressed transplant recipients. A key predisposing factor for opportunistic fungal infections is impaired adaptive immunity. However, in the absence of adaptive immunity, we found that osteopontin (OPN) plays a critical role in defense against an opportunistic fungus, Pneumocystis, which causes Pneumocystis pneumonia (PCP). The finding suggested that innate immunity alone can make a significant difference in resistance against fungi. Involvement of OPN in anti-fungal immunity was suggested by several previous studies, but the mechanism is not known. Although OPN has been studied as an extracellular molecule (secreted OPN;sOPN), our preliminary data strongly suggested that a novel intracellular OPN isoform (iOPN) is the main player in OPN-mediated anti-fungal responses. The goal of this proposed research is to elucidate the mechanism by which OPN protects immunocompromised hosts from Pneumocystis infection. To achieve the goal, we will test the following central hypothesis in this proposal: iOPN enhances anti-fungal innate immunity, and it does so by participating in forming fungal pattern recognition receptor (PRR) clusters and in transducing signals from the receptors as a cytoplasmic adaptor protein. Here, we will pursue the following specific aims:
(Aim 1) Elucidate the mechanism by which iOPN participates in fungal PRR cluster formation, (Aim 2) Elucidate the mechanism by which iOPN plays a role in signal transduction of fungal PRRs, and (Aim 3) Determine whether fungal clearance is enhanced by DCs and macrophages that express iOPN.
In Aim 1 and 2, we will use biochemical and cell biological approaches to elucidate how iOPN is involved in cellular responses upon fungal detection.
In Aim 3, we will use in vitro and in vivo approaches to test the iOPN- mediated clearance of Pneumocystis. Upon successful completion, our study will have an important positive impact on the research field of pathogen recognition by hosts. OPN is a well-studied protein, but virtually all the studies of OPN in the past focused on sOPN. Thus, understanding the biology of iOPN, a novel OPN isoform, has a great impact on the field of immunology. Furthermore, results from this study will provide better understanding in molecular mechanisms of fungal detection by innate immunity.
Opportunistic fungal infection is a common cause of serious morbidity and mortality in immunocompromised individuals, including AIDS patients, cancer patients under chemotherapy, and immunosuppressed transplant recipients. This study will use mouse model systems to better understand how our bodies can enhance resistance against fungal infection. Relevance of this study to public health, upon successful completion, is to apply findings from this study to develop new approaches in prophylaxis and treatment of fungal infection in immunocompromised patients.
|Aggarwal, Nupur; Barclay, William; Shinohara, Mari L (2018) Understanding mechanisms underlying the pathology of immune reconstitution inflammatory syndrome (IRIS) by using animal models. Curr Clin Microbiol Rep 5:201-209|
|Shinohara, Mari L (2017) Yes, research matters. PLoS Pathog 13:e1006420|
|Singh, Nina; Inoue, Makoto; Osawa, Ryosuke et al. (2017) Inflammasome expression and cytomegalovirus viremia in critically ill patients with sepsis. J Clin Virol 93:8-14|
|Xu, Shengjie; Shinohara, Mari L (2017) Tissue-Resident Macrophages in Fungal Infections. Front Immunol 8:1798|
|Kanayama, Masashi; Xu, Shengjie; Danzaki, Keiko et al. (2017) Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin. Nat Immunol 18:973-984|
|Schmidt, Elyse A; Fee, Brian E; Henry, Stanley C et al. (2017) Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem 292:4651-4662|
|Inoue, Makoto; Chen, Po-Han; Siecinski, Stephen et al. (2016) An interferon-?-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage. Nat Neurosci 19:1599-1609|
|Kanayama, Masashi; Shinohara, Mari L (2016) Roles of Autophagy and Autophagy-Related Proteins in Antifungal Immunity. Front Immunol 7:47|
|Kanayama, Masashi; Danzaki, Keiko; He, You-Wen et al. (2016) Lung inflammation stalls Th17-cell migration en route to the central nervous system during the development of experimental autoimmune encephalomyelitis. Int Immunol 28:463-9|
|Danzaki, Keiko; Kanayama, Masashi; Alcazar, Oscar et al. (2016) Osteopontin has a protective role in prostate tumor development in mice. Eur J Immunol 46:2669-2678|
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