Background Major depressive disorder (MDD) and its most severe phenotype, major dysmood disorder (MDMD), are distinguished by the activation of the immune-inflammatory response system, T cell activation, and a relative T regulatory cell suppression. Nevertheless, these immune data were not used to characterize the features of the immune protein-protein interaction (PPI) network of MDMD.

Objectives To identify the network’s nodes and bottlenecks as well as the biological processes that are overrepresented in the PPI network, we conducted PPI network, annotation, and enrichment analyses.

Results The PPI network analysis has identified the following backbone genes: tumor necrosis factor-α (TNF), interleukin (IL)6, CXCL12, CXCL10, CCL5, cluster of differentiation (CD)4, CD8A, human leukocyte antigen (HLA)-DR, and FOXP3. A “cellular and defense response”, an “immune response system response”, and “a viral process that involves viral protein interaction with cytokines and cytokine receptors” were all highly associated with the network. The chemokine network and TNF and nuclear factor-κB (NFKB) pathways are additional biological pathways that are enriched in the PPI network. Molecular complex detection extracted one component from the data, including viral protein interaction with cytokine and cytokine receptors and “regulated by RELA” (an NFKB subunit).

Conclusions Viral processes may underlie the activation of T cells and the cytokine and chemokine networks that are associated with MDMD. Future research on the pathogenesis of MDMD and MDD should examine whether and which viral infections are associated with the onset of these conditions, or whether viral reactivation is associated with the recurrence of illness.

The authors have declared no competing interest.

The C2F program at Chulalongkorn University in Thailand, grant number 64.310/436/2565 to AFA, the Thailand Science Research, and Innovation Fund at Chulalongkorn University (HEA663000016), and a Sompoch Endowment Fund (Faculty of Medicine) MDCU (RA66/016) to MM all provided funding for the project.

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:

This study involves a secondary data analysis using open, deidentified, and non-coded data sets so exempting it from IRB approval as non-human subjects research. The utilized data are derived from two case-control investigations (Almulla, Abbas Abo Algon et al. 2024, Maes, Zhou et al. 2024). Both case-control studies received approval from the local Institutional Review Boards, and all participants furnished signed informed consent before their participation in the study. The Institutional Review Board of the College of Medical Technology of the Islamic University of Najaf, Iraq, approved the study under Document No. 18/2021. The research procedure by Maes et al. (2024) was sanctioned by the Institutional Review Board of Chulalongkorn University, Faculty of Medicine, Bangkok, Thailand (#528/63).

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

↵* Co-joint first authors;

Michael Maes Google Scholar profile: Michael Maes: dr.michaelmaeshotmail.com, Kitiporn Plaimas: kplaimasgmail.com, Apichat Suratanee: apichat.ssci.kmutnb.ac.th, Yingqian Zhang: 18190727710163.com, Jing Li: lijingjingjing222163.com

MM and AFA designed the study. MM, KP and AS conducted the studys statistical analysis. MM. wrote the first draft of the paper AFA, KP, AS, YZ, and JL further edited the paper. All authors have read and approved the final manuscript. AS was funded by National Science, Research and Innovation Fund (NSRF), and King Mongkuts University of Technology North Bangkok (Project no. KMUTNB-FF-67-B-24).