Methods of Controlling Invasive Fungal Infections Using CD8+ T Cells

Abstract

Invasive fungal infections (IFIs) cause high rates of morbidity and mortality in immunocompromised patients. Pattern-recognition receptors present on the surfaces of innate immune cells recognize fungal pathogens and activate the first line of defense against fungal infection. The second line of defense is the adaptive immune system which involves mainly CD4+ T cells, while CD8+ T cells also play a role. CD8+ T cell-based vaccines designed to prevent IFIs are currently being investigated in clinical trials, their use could play an especially important role in acquired immune deficiency syndrome patients. So far, none of the vaccines used to treat IFI have been approved by the FDA. Here, we review current and future antifungal immunotherapy strategies involving CD8+ T cells. We highlight recent advances in the use of T cells engineered using a Sleeping Beauty vector to treat IFIs. Recent clinical trials using chimeric antigen receptor (CAR) T-cell therapy to treat patients with leukemia have shown very promising results. We hypothesized that CAR T cells could also be used to control IFI. Therefore, we designed a CAR that targets β-glucan, a sugar molecule found in most of the fungal cell walls, using the extracellular domain of Dectin-1, which binds to β-glucan. Mice treated with D-CAR+ T cells displayed reductions in hyphal growth of Aspergillus compared to the untreated group. Patients suffering from IFIs due to primary immunodeficiency, secondary immunodeficiency (e.g., HIV), or hematopoietic transplant patients may benefit from bioengineered CAR T cell therapy.

In silico Design of a Multivalent Vaccine Against Candida albicans

“…Antibody response to C. albicans is ideal to target carbohydrate moieties on the fungal cell wall, as well as some secreted proteins (secreted aspartyl proteinase or SAP 52 ) and has been shown to be effective in providing resistance against IC 53 . Although Tc play a minor role in natural immunological defense against candida and have not been studied much, previous studies show that Tc are effective in controlling fungal infection post-vaccination [54][55][56] . Therefore, a combination of strong humoral and cell-mediated immune responses is likely to confer an effective immune response against pathogenic candida.…”

Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: Case report and review of the literature

“…This combination is an attractive option since most transplant recipients already receive tacrolimus as part of their immunosuppression regimen . Immunotherapies for invasive fungal infections are intriguing interventions but are in their relative infancy . Vaccination has shown promise in the treatment of recurrent vulvovaginal candidiasis but it remains to be seen if this protection extends to invasive fungal infections …”

Glucuronoxylomannan in theCryptococcusspecies capsule as a target for CAR+T-cell therapy

“…Moreover, CD8 + T cells differentiate into Tc1 and Tc17 cells, which produce IFN-γ and IL-17, contributing to the recruitment of innate immune cells involved in antifungal defense. The major mechanism that CD8 + T cells use to control fungal infections is the targeted release of cytotoxic factors that act directly on fungi, such as perforin, granulysin, and granzyme [9]. The antifungal activity of adoptive T-cell therapy can be improved by redirecting T-cell specificity using a CAR that recognizes specific fungal antigens.…”

“…In addition, mice infected with C. gattii displayed reduced dendritic cell-mediated Th1/Th17 immune responses [8]. Although several fungal vaccine studies have demonstrated an essential role for CD8 + T cells in destroying host cells harboring intracellular fungus[9], not many studies have used CD8+ T cells for direct killing of extracellular fungal infection.…”