Microfilaremic loiasis is associated with T cell hyporesponsiveness against SARS CoV-2

1. Problem Statement and Background

Loiasis, caused by the filarial parasite Loa loa (African eyeworm), is endemic to Central and West Africa. While historically considered benign, it is increasingly linked to significant morbidity and mortality. The infection presents in two distinct clinical forms:

• Microfilaremic: Presence of circulating L. loa microfilariae in the blood.
• Occult (Amicrofilaremic): History of eye worm migration without detectable microfilariae.

Helminth infections are known to induce immune modulation, typically skewing responses toward a Th2 profile and enhancing regulatory pathways (e.g., IL-10, TGF-β), which can suppress effector T cell responses to heterologous antigens. However, the specific impact of chronic L. loa infection on antiviral immunity, particularly against SARS-CoV-2, remains poorly understood. This study aimed to investigate whether chronic loiasis impairs immune responses to SARS-CoV-2 in unvaccinated individuals.

2. Methodology

Study Design and Population:

• Type: Cross-sectional study conducted between 2022 and 2024 in Lambaréné and surrounding rural areas of Gabon.
• Participants: 192 unvaccinated adults (≥18 years) with no pregnancy.
• Grouping: Participants were categorized into three groups based on L. loa status:
  1. Microfilaremic (n=43): Detectable microfilariae in blood smears.
  2. Occult Loiasis (n=59): Negative blood smear but positive history of eyeworm migration (RAPLOA).
  3. No Active Loiasis (n=90): Negative blood smear and negative RAPLOA history.

Data Collection and Diagnostics:

• Parasitology: L. loa status confirmed via Giemsa-stained thick blood smears (accounting for diurnal periodicity). Stool and urine samples were analyzed for co-infections (malaria, soil-transmitted helminths, Schistosoma, etc.).
• Hematology: Full blood counts and leukocyte differentiation were performed.
• SARS-CoV-2 Immune Assays:
  • Humoral Response: IgG antibodies against Spike (S1) and Nucleocapsid (NCP) proteins were quantified using Euroimmun ELISA kits.
  • Cellular Response: IFN-γ production in response to SARS-CoV-2 Spike antigen was measured using the Quan-T-Cell SARS-CoV-2 kit (interferon-gamma release assay).
• Controls: 30 pre-pandemic samples from the same region were tested to assess baseline cross-reactivity.

Statistical Analysis:

• Non-parametric tests (Wilcoxon rank-sum, Kruskal-Wallis) were used for group comparisons.
• Multiple linear regression models adjusted for age and sex were employed to assess confounding.
• False Discovery Rate (FDR) correction was applied for multiple comparisons.

3. Key Results

Hematological Findings:

• Eosinophilia: Microfilaremic individuals exhibited significantly higher absolute and relative eosinophil counts compared to occult and non-infected groups (Median absolute: 0.9 G/L vs. 0.3 G/L; p=0.001).
• Leukocytes: Microfilaremic participants had significantly higher total leukocyte counts (6.4 G/L vs. 5.0 G/L; p=0.001).
• Hemoglobin: No significant differences were observed between groups.

SARS-CoV-2 Immune Responses:

• Antibody Responses (Humoral): There were no significant differences in anti-Spike (S1) or anti-Nucleocapsid (NCP) IgG levels across the three groups. The presence of microfilaremia did not impair the humoral response.
• T Cell Responses (Cellular):
  • IFN-γ Levels: Microfilaremic individuals showed significantly reduced SARS-CoV-2-specific IFN-γ responses compared to non-microfilaremic participants (Median: 870 mIU/mL vs. 1461 mIU/mL; p=0.01 unadjusted, p=0.031 adjusted).
  • Subgroup Analysis: The reduction in IFN-γ was specifically significant when comparing Microfilaremic vs. Occult groups (870 vs. 1479 mIU/mL; p=0.015 unadjusted, p=0.012 adjusted).
  • Correlation: A weak but significant negative correlation was found between absolute IFN-γ levels and absolute eosinophil counts (rho = -0.17, p=0.045), as well as between IFN-γ and microfilaremia density.

4. Key Contributions

• Selective Immune Modulation: The study provides evidence that chronic microfilaremic loiasis induces a selective impairment of cellular immunity (T cell hyporesponsiveness) while preserving humoral immunity (antibody production) against SARS-CoV-2.
• Differentiation of Clinical States: It highlights a distinct immunological divergence between microfilaremic and occult loiasis, suggesting that the presence of circulating microfilariae is the critical driver of T cell suppression, rather than mere exposure to the parasite.
• Mechanistic Insight: The findings support the hypothesis that chronic filarial infections drive regulatory pathways (potentially involving Tr1 cells and IL-10) that dampen proinflammatory Th1 responses (IFN-γ) without affecting B-cell mediated antibody responses.

5. Significance and Implications

• Vaccine and Therapeutic Efficacy: In endemic regions, microfilaremic individuals may have suboptimal T cell responses to viral vaccines or infections, potentially affecting the durability of protection or the ability to clear viral infections, even if antibody titers appear normal.
• Public Health Strategy: The results underscore the need to consider helminth co-infections when designing vaccination strategies or interpreting immune correlates of protection in tropical regions.
• Future Research: The study identifies a critical gap in understanding the mechanisms of T cell suppression in filariasis. It calls for longitudinal studies to determine if antiparasitic treatment restores T cell function and for deeper phenotyping of regulatory T cells (e.g., Tr1, LAG3+CD49b+) in these populations.

Limitations:
The cross-sectional design limits causal inference. The study could not fully control for prior viral exposure history or other environmental factors that might influence the host's infection state (microfilaremic vs. occult). Additionally, the study did not assess neutralizing capacity or IgG subclass distribution.