Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection 2023 Ambikan et al

Significance
Our study identified a dysregulation and hyperactivity of the critical metabolic process of the central carbon and energy metabolism, and metabolic flux related to the amino acid metabolism during the acute progressive phases of infection can promote the exhausted phenotype upon recovery leading to postviral fatigue syndrome in CCHFV (Crimean-Congo hemorrhagic fever virus) infection.

Abstract
Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown.

Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection.

The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

Open access, https://www.pnas.org/doi/10.1073/pnas.2304722120

 

"Several viral infections, like Dengue fever (28), WNV (29), SARS-CoV-2 (30), EVDs (31), and Marburg viruses (32), impact the neuropsychiatric systems upon complications present PVF, which may linger for months after infection. The PVF presents similar to chronic fatigue syndrome, characterized by fatigue/weakness, headache, dizziness, musculoskeletal pain, and cognitive and sleep disorders, and could be linked to dysregulated CCM (33) and microbial dysbiosis impacting the gut–brain axis (34). It could be associated with virus-specific pathophysiologic changes, immunologic aberrations, and inflammatory damage during acute infection.

Several clinical studies have reported the acute phase of symptoms in CCHF patients. However, the clinical manifestations of CCHF during the postacute phase have not been widely investigated. During the convalescent phase (10 to 20 d after symptoms onset), the survivors experience fatigue, tachycardia, hair loss, neuritis, hearing loss, loss of memory, and bradycardia for a long time (35). During the convalescent period, 83% of CCHF patients in our cohort reported having fatigue, evidenced by a relationship between the PVF and metabolic insufficiency upon recovery. Herein, we postulate that the high prevalence of fatigue among CCHF patients, both in the acute and convalescent phases, can be explained partly by dysregulated metabolic pathways during infection, as reported in COVID-19 (36, 37). A better understanding of the immuno-metabolic mechanism of the PVF in CCHF patients can identify therapeutic targets for better and faster recovery."

 

A better understanding of the immuno-metabolic mechanism of the PVF in CCHF patients can identify therapeutic targets for better and faster recovery.

Bring it on!