Zika Patients May Face a Poorer COVID-19 Prognosis
Clinical Relevance
Orthoflavivirus and SARS-CoV-2 infections can cause acute viral diseases. Although research remains limited, coinfections involving SARS-CoV-2 and orthoflaviviruses, including Zika virus (ZIKV), have been reported in Mexico, raising concerns about their potential coinfection in other regions with a history of Zika epidemics, such as Brazil. Because these infections may present with overlapping clinical manifestations, coinfection could complicate differential diagnosis, delay appropriate clinical management, and potentially affect disease progression and patient outcomes. However, the clinical characteristics, severity, and prognostic implications of ZIKV and SARS-CoV-2 coinfection remain poorly understood. Investigating this potential interaction is therefore clinically relevant to improving diagnostic awareness, identifying patients who may require closer monitoring, and clarifying whether pre-existing or concurrent ZIKV infection influences the clinical course and prognosis of COVID-19.
Zika-Infected Patients May Experience Worse COVID-19 Outcomes
Briefly, I reanalyzed proteomics profile of ZIKV-infected cells and identified at least two potential players that may contribute to a worsening COVID-19 prognosis. ZIKV significantly upregulated protein levels of interferon-stimulated gene 15 (ISG15) and protein transport protein Sec61 subunit beta (SEC61B) (Fig. A, Heatmap).
ISG15 is an interferon-inducible ubiquitin-like protein that plays an important role in the innate immune response against viral infections through ISGylation, a process in which ISG15 is covalently conjugated to other proteins. This modification can regulate the activity, stability, and subcellular localization of components of the RIG-I-like receptor and interferon signaling pathways, including MDA5, IRF3, and STAT1, thereby modulating interferon production and downstream antiviral responses. In addition, ISGylation can also directly interfere with viral protein functions and inhibit viral replication. On the other hand, the SARS-CoV-2 papain-like protease (PLpro) exhibits strong de-ISGylating activity, cleaving ZIKV-associated ISG15 from innate immunity components and elevating free (unconjugated) ISG15 levels. Independent of ZIKV infection, SARS-CoV-2 infection may also promote the accumulation of free ISG15 through alterations in host ISG15 expression and processing. Free ISG15 can be unconventionally secreted into extracellular space. There, it promotes macrophage M1 polarization and drives pro-inflammatory cytokine overproduction (hyperinflammation) associated with severe COVID-19 immunopathology (Fig. B).
A multi-organ proteomic study of COVID-19 autopsies has noted elevated SEC61B expression, which may be linked to cellular stress responses and fibrosis. As a component of the Sec61 protein translocation complex in the endoplasmic reticulum (ER), SEC61B contributes to the translocation and membrane insertion of newly synthesized proteins. Therefore, SEC61B may also influence SARS-CoV-2 replication by supporting viral protein biogenesis and replication-associated membrane structure, although this specific notion requires further investigation. Recent studies have highlighted the involvement of the Sec61 machinery in the insertion of SARS-CoV-2 nonstructural protein nsp3 into the ER membrane, supporting viral replication. Moreover, pharmacological inhibition of Sec61 machinery with apratoxin S4 significantly reduced SARS-CoV-2 replication. Based on these findings, it is intriguing to speculate that SEC61B may facilitate SARS-CoV-2 replication through its involvement in the Sec61 translocon, thus contributing to increased viral load and a poorer COVID-19 prognosis (Fig. C).
Take-Home Hypothesis & Clinical Implication
This hypothesis proposes ZIKV-associated changes in host proteins expression could influence COVID-19 pathogenesis and prognosis through ISG15-associated inflammation and SEC61B-associated viral replication. These proposed mechanisms provide a testable framework for future experimental and clinical investigations. The potential interaction between ZIKV and SARS-CoV-2 also underscores the importance of considering arboviral coinfections when evaluating patients with COVID-19 in regions where ZIKV circulates. Furthermore, SEC61B and circulating ISG15 warrant further investigation as a therapeutic target and potential biomarker of COVID-19 outcomes in patients with Zika.
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