ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Virology
Unraveling the Dual Immunomodulatory and Immunogenic Roles of the Central Conserved Cysteine-Rich Region in Respiratory Syncytial Virus G Protein
Juan Gutman 1
Ana Luz Paletta 2
Federico Birnberg Weiss 3
Cecilia Arahi Prato 2
Analía Boudgouste 1
Carla Jimena Goldin 1
Santiago Sastre 4
Alana Byrne 1
Pablo Pakciarz 5
Fernando Polack 6
Julia Dvorkin 5
Ari Zeida 4
Mauricio Tomas Caballero 5
Veronica Landoni 3
Gabriela Cristina Fernandez 3
María Virginia Tribulatti 2
Damian Alvarez-Paggi 1
Sebastian Esperante 1
1. Centro de Rediseño e Ingeniería de Proteínas (CRIP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
2. CONICET Institute of Biotechnological Research (IIB-INTECH), San Martín, Argentina
3. Instituto de Medicina Experimental, Buenos Aires, Argentina
4. Universidad de la Republica Facultad de Quimica, Montevideo, Uruguay
5. Centro Infant de Medicina Traslacional (CIMeT), Escuela de Bio y Nanotecnología, Universidad Nacional de San Martín, Buenos Aires, Argentina
6. Fundacion Infant, Buenos Aires, Argentina
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Abstract
Respiratory syncytial virus (RSV) causes severe respiratory disease in infants and high-risk adults, in part by subverting host immunity. The RSV G glycoprotein's central conserved cysteine rich domain (CCD) contains a CX3C motif implicated in immune modulation, but the relationship between its redox state, structural conformation, and immune modulatory function remains unclear. In this study, we recombinantly expressed a CCD-derived peptide (Gpep, residues 149–196), determined its redox-dependent folding by reversed-phase HPLC (RP-HPLC) and biophysical analyses, and assessed its function using murine dendritic cell and human neutrophil assays alongside pediatric serology. Kinetic analyses by RP‑HPLC and biophysical techniques showed that reduced Gpep rapidly folds through a predominant intermediate to yield an oxidized monomer; conversely, higher concentrations drive intermolecular disulfide isomerization and covalent oligomer formation. Functionally, Gpep inhibited dendritic cell activation elicited by both LPS-and UV-inactivated RSV. In addition, Gpep suppressed multiple human neutrophil responses, including chemotaxis, CD11b upregulation, reactive oxygen species production, myeloperoxidase release, and NET formation, without inducing cytotoxicity. In contrast, oligomerized Gpep lacked immunosuppressive activity. Serological analysis of an ambulatory pediatric cohort (0–72 months) showed a transient increase in the anti-F/anti-G IgG ratio following early RSV exposures, consistent with preferential maturation of F-directed responses. We propose a redox‑dependent immune‑evasion model in which secreted, monomeric G mediates transient immunosuppression that is halted by disulfide‑driven oligomerization of membrane‑bound G and F proteins. These findings support a mechanistic association between the redox state of RSV G, its oligomeric behavior, and its immunomodulatory properties.
Summary
Keywords
host/pathogen interactions, Immunomodulation, Immunopathogenesis, redox, RSVG central conserved domain
Received
22 January 2026
Accepted
19 February 2026
Copyright
© 2026 Gutman, Paletta, Birnberg Weiss, Prato, Boudgouste, Goldin, Sastre, Byrne, Pakciarz, Polack, Dvorkin, Zeida, Caballero, Landoni, Fernandez, Tribulatti, Alvarez-Paggi and Esperante. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Damian Alvarez-Paggi; Sebastian Esperante
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