The Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal Infection

Abstract

Background: Invasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern-recognition receptors (e.g., Toll-like receptors, C-type lectins or Scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a non-redundant component of the antifungal host immune response that binds to fungal β-glucans. Methods: antifungal properties of the soluble ectodomain of human CD5 (shCD5) were assessed in vivo in experimental models of systemic fungal infection induced by pathogenic species (Candida albicans and Cryptococcus neoformans). In vitro mechanistic studies were performed by means of fungal-spleen cell co-cultures. Results: shCD5-induced survival of lethally infected mice was dose and time-dependent and concomitant with reduced fungal load and increased leukocyte infiltration in primary target organ. Additive effects were observed in vivo after shCD5 was combined with sub-optimal doses of fluconazole. Ex vivo addition of shCD5 to fungal-spleen cell co-cultures increased release of pro-inflammatory cytokines involved in antifungal defence (TNF-α and IFN-γ) and reduced the number of viable C. albicans. Conclusions: The results prompt further exploration of the adjunctive therapeutic potential of shCD5 in severe invasive fungal diseases.

Soluble CD5 and CD6: Lymphocytic Class I Scavenger Receptors as Immunotherapeutic Agents

“…These results prompt further exploration of shCD5 as adjunctive immunotherapy to reduce the adverse effects associated with current anti-mycotic drugs without compromising their efficacy in case of drug resistance, and at the same time, to expand their antifungal spectrum. The lack of shCD5 efficacy, observed when treating C. albicans-infected immunodeficient NOD scid gamma (NSG) mice, supports the notion that an intact immune system is necessary for optimal survival following shCD5 infusion [55].…”

“…Such prophylactically infused mice also showed decreased toxicity score, peritoneal leukocyte infiltration, pro-inflammatory cytokine production, and liver myeloperoxidase activity [12]. Recent studies have further shown dose-and time-dependent therapeutic effects of rshCD5 infusion in mouse models of systemic infection by pathogenic fungal species (C. albicans and C. neoformans) [55]. Higher rshCD5-induced survival of lethally infected mice was concomitant with reduced fungal load, increased IFN-γ mRNA levels and increased lymphoid (NK and B) and myeloid (dendritic, macrophage and granulocyte) cell infiltration in primary target organs (i.e., kidney for C. albicans) [55].…”

“…Recent studies have further shown dose-and time-dependent therapeutic effects of rshCD5 infusion in mouse models of systemic infection by pathogenic fungal species (C. albicans and C. neoformans) [55]. Higher rshCD5-induced survival of lethally infected mice was concomitant with reduced fungal load, increased IFN-γ mRNA levels and increased lymphoid (NK and B) and myeloid (dendritic, macrophage and granulocyte) cell infiltration in primary target organs (i.e., kidney for C. albicans) [55]. Furthermore, ex vivo studies showed that addition of rshCD5 to fungus-splenocyte co-cultures increased pro-inflammatory cytokine release involved in antifungal defense (TNF-α and IFN-γ) and reduced the number of viable C. albicans.…”

Recombinant CD5 and CD6 Ectodomains Induce Antiparasitic and Immunomodulatory Effects in Secondary Cystic Echinococcosis

“…Besides their lymphocyte immunomodulatory functions, CD5 and CD6 also exhibit broad pathogen-recognition receptor properties [4]. Accordingly, infusion of their human recombinant soluble ectodomains-rshCD5 and/or rshCD6-exerts prophylactic/ therapeutic potential in murine models of fungal, bacterial and parasitic infections [5][6][7][8].…”