CXCL13/CXCR5 Chemokine Axis Promotes CXCR5 ⁺ CD19 ⁺ B-Cell and Follicular/Effector CXCR5 ⁺ CD4 ⁺ T-Cell Responses in the Lungs Associated with Protection from Severe and Fatal COVID-19 Following Infection with Pathogenic SARS-CoV-2 Delta Variant

Chemokines play an important role in shaping lung innate and adaptive immunity to pulmonary infections and diseases. However, the role of CXC ligand 13 (CXCL13), a chemokine homeostatically produced by various lung cell types, in the protection from SARS-CoV-2 infection and disease remains controversial. Some studies reported that asymptomatic patients who survived severe COVID-19 had CXCL13-dominated mucosal immune responses in the lungs early during infection. In contrast, other studies reported that a high level of CXCL13 was associated with severity and mortality in COVID-19 patients. In this study, to determine the direct role of CXCL13 in SARS-CoV-2 infection and disease, we generated CXCL13 ^-/- K18-hACE2 mice, that are both transgenic for ACE2 and deficient in CXCL13 and compared their infection and COVID-19-like disease symptoms with those in wild-type K18-hACE2 transgenic mouse littermates following intranasal inoculation with the pathogenic SARS-CoV-2 delta variant (B.1.617.2). Compared to age- and gender-matched SARS-CoV-2 infected wild-type K18-hACE2 mice, SARS-CoV-2 infected CXCL13 ^-/- K18-hACE2 deficient mice exhibited ( i ) higher viral load in the lungs; ( ii ) severe COVID-19-like lung pathology; ( iii ) exacerbated weight loss; ( iv ) increased mortality. The apparent severe COVID-19-like symptoms in CXCL13 ^-/- K18-hACE2 deficient mice were associated with: ( i ) significantly lower frequencies of functional lung-resident C-X-C chemokine receptor 5 ⁺ (CXCR5) ⁺ CD19 ⁺ B cells, follicular CXCR5 ⁺ CD4 ⁺ helper T cells (Tfh cells), and IFN-ψ ⁺ TNF-α ⁺ GzmB ⁺ Ki67 ⁺ effector CD4 ⁺ Th ₁ cells; and ( ii ) a significant reduction in the levels of SARS-CoV-2-Spike specific Th1 associated IgG ₁ and IgG _2b antibody isotypes. These findings corroborate previous human reports suggesting a critical role of the CXCL13/CXCR5 chemokine axis in the protective B- and T-cell mucosal immunity to SARS-CoV-2 infection and disease, offering a potential new immunotherapeutic target for treatment.