Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients

In the 2018 yellow fever (YF) outbreak in Brazil, we generated new transcriptomic data and combined it with clinical and immunological data to decode the pathogenesis of YF. Our analysis of 79 patients highlighted distinct gene expression patterns between acute YF infections, other viral infections, and the milder infection induced by the live-attenuated YF-17D vaccine. We identified a critical role for low-density, immature neutrophils in severe outcomes, marked by the downregulation of genes such as PADI4, CSF3R, and ICAM1 in deceased patients. These genes are essential for neutrophil migration and maturation, suggesting their pivotal role in disease progression. Furthermore, our study revealed a complex interaction among inflammation-related genes: increased expression of CXCL10 in the acute phase was accompanied by decreased expression of IL-1b and an increase in IL1R2, a decoy receptor that binds to IL-1 to inhibit its activity. The diminished expression of HLA class II genes suggests an impairment in antigen presentation. These insights underscore the delicate balance of immune responses in YF pathogenesis and provide a foundation for future therapeutic and diagnostic advancements in managing YF. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by Bill & Melinda Gates Foundation, FAPESP, HCFMUSP, and USP. HIN is funded by FAPESP (grant numbers: #2017/50137-3, 2012/19278-6, 2018/14933-2, 2018/21934-5, and 2013/08216-2) and CNPq (313662/2017-7). We are particularly thankful to the following grants for fellows: ANAG (FAPESP Process 2019/13880-5), VEM (FAPESP Process 2019/16418-0), APV (FAPESP Process 2019/27146-1), MVT (FAPESP Process 2019/13713-1 and 2016/01735-2) and the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) (PhD Scholarships to CAC and MPM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received ethical approval from the ethical review boards at the Institute of Infectology "Emilio Ribas" and Hospital das Clinicas, University of Sao Paulo (CAPPesq: 15477; CAAE: 59542216.3.1001.0068). All patients provided consent for participation, or their legal representatives did so when required, before being included in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated in the current study are deposited at https://www.ncbi.nlm.nih.gov/BioProject (BioProject: PRJNA1017409) and will be made publicly accessible upon publication of the article in a peer-reviewed journal.