Newswise — Philadelphia, June 1, 2023 –Immunocompromised individuals face an elevated risk of experiencing severe or prolonged illness when infected with COVID-19. To mitigate its impact on multiple organs, comprehending the systemic immune response becomes crucial for ongoing research endeavors. A recent study, featured in The American Journal of Pathology published by Elsevier, investigated SARS-CoV2-infected mice and identified lymphoid depletion lesions in the spleen. These findings have the potential to serve as a basis for developing innovative therapies aimed at restoring impaired antigen-presenting cell (APC) functions in humans. By triggering the cellular immune response, these novel treatments may hold promise in reducing the severity of COVID-19.

The severity of COVID-19 can range significantly, from asymptomatic cases to severe illness with life-threatening complications. Dysregulated immune responses have been linked to an increased risk of developing severe disease in patients. COVID-19 affects not only the respiratory system but also other organs, resulting in long-term complications and, in severe cases, multi-organ dysfunction. Notably, the presence of low lymphocyte counts (lymphopenia) and depletion of lymphoid tissues has been associated with unfavorable disease outcomes.

Dr. Je Kyung Seong, DVM, PhD, from the Korea Mouse Phenotyping Center (KMPC), Seoul National University, and Dr. Jun Won Park, DVM, PhD, from the College of Biomedical Science, Kangwon National University, who spearheaded the investigation, elucidated, "The precise mechanisms underlying the progression of severe disease in COVID-19 are not yet fully understood. This is partly due to the challenges in assessing immunological factors in clinical samples, which can be influenced by various factors such as underlying medical conditions, age, gender, environmental exposures, and dietary habits."

The researchers further emphasized, "It is imperative to investigate the factors that contribute to the increased risk of severe disease, particularly in terms of the immunological dynamics, by conducting well-controlled experiments using animal models. This approach is crucial for comprehending the mortality rates and the immunological factors that play a role in disease severity. Therefore, gaining a comprehensive understanding of the systemic immune response, extending beyond lung-related lesions, is of utmost importance in research endeavors aimed at mitigating the impact of COVID-19 on multiple organs and mitigating its long-term consequences."

This study employed transgenic mouse models expressing human angiotensin-converting enzyme 2 (K18-hACE2), which renders them susceptible to SARS-CoV-2 infection, the virus responsible for causing COVID-19. The objective was to explore the features and factors contributing to lethality linked with the observed lymphoid depletion in COVID-19.

Dr. Seong highlighted, "The K18-hACE2 mouse model has been widely utilized in preclinical trials aimed at developing treatments and vaccines for COVID-19. Our research team has conducted numerous preclinical studies using this model. Through these investigations, we have identified a significant association between the mortality rate, fatal brain infections, and the observed lymphoid depletion in the spleens of these mice."

Dr. Park further emphasized, "Since comparable splenic lesions are observed in severe COVID-19 patients, it is of utmost importance to investigate and characterize the lymphoid depletion in this mouse model that leads to lethality. By doing so, we can gain valuable insights into the factors that contribute to mortality in COVID-19 patients and facilitate the development of effective therapies to mitigate these outcomes."

The mice that were infected displayed a wide spectrum of disease severity, which was assessed based on parameters such as weight, temperature, lung pathology, spleen pathology, and brain infection. The researchers examined the correlation between these factors to determine the lethality associated with COVID-19 in the mouse model. The findings revealed that, apart from lung lesions, the viral load in the brain emerged as a significant determinant of mortality in this particular mouse model.

The collective findings highlight the significance of lymphoid depletion lesions observed in the spleen as an essential factor associated with mortality rates. Notably, lymphoid depletion accompanied by impaired antigen-presenting cell (APC) function was a distinctive characteristic observed in SARS-CoV-2 variants originating from Wuhan and Delta, but not in other infections like Omicron and influenza A. Furthermore, this particular feature held the greatest prognostic value for disease severity in mice infected with the Wuhan and Delta variants.

Dr. Seong remarked, "Therefore, our study provides evidence that lymphoid depletion accompanied by suppressed antigen-presenting cell (APC) function is a defining characteristic of the lethality observed in COVID-19 mouse models."

Dr. Park noted, "Our study lays the foundation for potential therapies that could restore impaired antigen-presenting cell (APC) functions in individuals with COVID-19. By enhancing APC functionality, these novel therapies may hold promise in mitigating the severe progression of the disease."

Based on their findings, the researchers recommend the evaluation of the spleen in K18-hACE2 mice as a means to assess the effectiveness of vaccines and therapeutics in preclinical testing. This approach can provide valuable insights into the efficacy of potential interventions for COVID-19.

Journal Link: The American Journal of Pathology