Cross-reactivity between vaccine antigens from the chitin deacetylase protein family improves survival in a mouse model of cryptococcosis

Abstract

Meningitis due to the fungal pathogen Cryptococcus neoformans is estimated to cause nearly 200,000 deaths annually, mostly in resource-limited regions. We previously identified cryptococcal protein antigens which, when delivered in glucan particles, afford vaccine-mediated protection against an otherwise lethal infection. Many of these proteins exhibit significant homology to other similar cryptococcal proteins leading us to hypothesize that protection may be augmented by immunologic cross-reactivity to multiple members of a protein family. To examine the significance of protein cross-reactivity in vaccination, we utilized strains of Cryptococcus that are genetically deficient in select antigens, yet are still lethal in mice. Vaccination with a protein without homologs (e.g., Mep1 and Lhc1) protected against challenge with wild-type Cryptococcus, but not against a deletion strain lacking that protein. Contrastingly, vaccination with a single chitin deacetylase (Cda) protein protected against the corresponding deletion strain, presumably due to host recognition of one or more other family members still expressed in this strain. Vaccination with a single Cda protein induced cross-reactive antibody and interferon-gamma (IFNγ) immune responses to other Cda protein family members. Paradoxically, we saw no evidence of cross-protection within the carboxypeptidase family of proteins. Factors such as in vivo protein expression and the degree of homology across the family could inform the extent to which vaccine-mediated immunity is amplified. Together, these data suggest a role for prioritizing protein families in fungal vaccine design: increasing the number of immune targets generated by a single antigen may improve efficacy while diminishing the risk of vaccine-resistant strains arising from gene mutations.

Promising whole‐cell vaccines against cryptococcosis

“…24 The GP-Cda1 vaccine also elicits IgG production that is crossreactive to family proteins, although future studies will reveal if this antibody-mediated immunity (AMI) or CD4 + T cell-independent cellular immunity is involved in the protection conferred by the GP-Cda1 vaccine. 66 After C. gattii R265 infection, the mortality is significantly improved in C57BL/6 mice immunized with GP-Cda1, which is similar to the result following C. neoformans KN99 infection; however, this life-prolonging effect against C. gattii R265 challenge was limited in BALB/c mice. 63 Since there are few subunit vaccines that are effective against both C. neoformans and C. gattii infections, it would be interesting to identify appropriate molecules that are common antigenic components of both pathogens and are still well expressed in the host environments.…”

“…This protection probably occurs via cellular immunity, including Th1 and Th17 response 24 . The GP‐Cda1 vaccine also elicits IgG production that is cross‐reactive to family proteins, although future studies will reveal if this antibody‐mediated immunity (AMI) or CD4 + T cell‐independent cellular immunity is involved in the protection conferred by the GP‐Cda1 vaccine 66 . After C. gattii R265 infection, the mortality is significantly improved in C57BL/6 mice immunized with GP‐Cda1, which is similar to the result following C. neoformans KN99 infection; however, this life‐prolonging effect against C. gattii R265 challenge was limited in BALB/c mice 63 .…”

Exploring gene signatures and regulatory networks in a rat model of sciatica: implications and validation in neuropathic pain

“…The elevated levels of IL-1β, MCP-1, and IL-6 in the spinal dorsal horn of the SCN-CCI group are consistent with the involvement of neuroinflammation in NP. These cytokines have been implicated in mediating glial activation, neuroinflammatory responses, and the sensitization of pain pathways ( Hester et al, 2022 ; Damiati et al, 2023 ; Paranga et al, 2023 ), and the increased activation of microglial cells observed in the SCN-CCI group further supports the role of neuroinflammation in NP pathophysiology. Microglial activation has been associated with releasing pro-inflammatory mediators and amplifying pain signaling ( Dheen et al, 2007 ; Smith et al, 2012 ).…”

Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines

“…The reason for the disparate results with the two adjuvants merits further study but could be due to differences in the potency of the adjuvants and the immune responses elicited. Cpd1, a carboxypeptidase family member with homology to human cathepsin A, partially protects mice from experimental cryptococcosis when delivered in GP vaccines [9, 10]. Due to concerns about molecular mimicry eliciting autoimmunity [38], we deleted the homologous region.…”

“…GPs possess a 1,3-β-glucan outer shell, promoting receptor-mediated uptake by antigen presenting cells and enhancing immune responses to encapsulated antigens [8]. Among the twenty-three cryptococcal recombinant proteins tested in murine models, chitin deacetylase protein 1 and 2 (Cda1, Cda2), barwin-like domain protein 4 (Blp4), and carboxypeptidase 1 (Cpd1) emerged as highly promising protein antigens that afford significant survival advantages following pulmonary challenge with a highly virulent C. neoformans strain in both BALB/c and C57BL/6 mouse lines [9, 10]. Moreover, vaccination with these antigens encased in GPs elicits robust antigen-specific T helper (Th) 1 and Th17 responses critical for vaccine-induced protection [11].…”