Exploring the Impact of Viral Infections on Lupus Development and Heterogeneity

Lupus is a chronic autoimmune disease in which the immune system mistakenly attacks the body’s own tissues. While genetic factors play a role, environmental triggers, particularly viral infections, are also believed to contribute to disease onset and progression. However, the specific viruses or viral components involved remain largely unknown, especially in Hispanic/Latinx and African American women, who are disproportionately affected by lupus and underrepresented in research studies.

This project aims to identify viral exposures that may increase the risk of developing lupus or influence the severity of the disease. We will analyze blood samples from Hispanic/Latinx and African American women with and without lupus using a cutting-edge technology called VirScan, which can detect past exposure to hundreds of viruses by measuring antiviral antibodies (i.e., blood proteins produced in response to infections). By comparing viral antibody patterns between cases and matched controls, we will identify viruses and viral peptides (i.e. small proteins) associated with lupus risk. We will also assess whether these exposures occurred before or after diagnosis and whether they are linked to specific clinical forms of lupus, such as lupus nephritis.

This research will provide the first comprehensive map of viral exposure and immune responses in lupus at both the virus and peptide level. Our findings may reveal new disease triggers, inform future prevention or treatment strategies, and help reduce longstanding disparities in autoimmune disease research by focusing on high-risk, historically underserved populations.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation, with a disproportionate burden among Hispanic/Latinx and African American women. Viral infections are believed to contribute to SLE pathogenesis, but their roles in disease risk and clinical subtypes, such as lupus nephritis (LN), a severe form affecting up to 50% of patients, remain incompletely understood. Most prior studies rely on post-diagnosis samples, leaving it unclear whether viral exposures precede disease onset or reflect underlying immune dysfunction. In addition, prior research has focused primarily on a small number of prevalent, persistent viruses, most notably Epstein-Barr virus (EBV) and parvovirus B19, while evidence for other viruses remains limited or inconsistent.

Our project aims to address these gaps. We hypothesize that specific viral exposures or viral peptides act as causal triggers or modifiers of lupus and its clinical heterogeneity. Our overarching goal is to generate a temporally informed, antigen-resolved map of viral exposures associated with lupus risk and subtype in Hispanic/Latinx and African American women.

Aim 1 will identify virus-level exposures associated with SLE and LN. We will analyze antibody responses to over 480,000 viral peptides using a high-throughput serological screening method (VirScan) applied to pre- and post-diagnosis plasma from 160 cases and 80 matched controls across two biobanks in the U.S. and Mexico. We will use statistical association and interaction analysis to test virus-disease associations and assess whether the strength of association varies by timing of sample collection (pre- vs. post-diagnosis) or clinical subtype (LN vs. non-LN).

Aim 2 will identify individual viral peptides and peptide clusters associated with lupus. Using quantitative peptide-level reactivity data, we will perform association testing at the individual peptide level, followed by sequence-based clustering to identify groups of cross-reactive or structurally similar peptides. As in Aim 1, we will evaluate whether associations differ by sample timing or clinical subtype to prioritize likely causal exposures.

This project represents the first seroepidemiologic study of viral exposures in lupus to combine high throughput viral profiling, peptide-resolution analysis, and temporally informed statistical modeling in two ethnically diverse, well-characterized cohorts. By addressing key limitations in the current literature and emphasizing both mechanistic interpretation and population relevance, this work will generate actionable insights into lupus pathogenesis and lay the groundwork for future prevention strategies and precision immunotherapy.