In a recently published article on the bioRxiv* preprint server, scientists from the USA and UK have described the significance of early inflammatory signaling pathways in determining the severity of coronavirus disease 2019 (COVID-19).
As of September 20, 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, has infected around 229 million people and claimed more than 4.69 million lives globally.
As a respiratory virus, SARS-CoV-2 primarily attacks respiratory epithelial cells and induces a wide variety of clinical outcomes. Besides viral mutations, host genetic variations play a significant role in shaping viral transmission and disease severity. Individuals who are genetically susceptible to an impaired immune response have been found to develop more severe COVID-19.
In the current study, the scientists have used genetically diverse mouse models to assess the impact of host genetics on the immune responses and COVID-19 severity.
The scientists crossed human angiotensin-converting enzyme 2 (ACE2)-expressing mice with a large panel of genetically distinct inbred mouse strains collectively called the Collaborative Cross (CC). The mice expressing human ACE2 (host cell receptor for SARS-CoV-2 entry) were used to establish SARS-CoV-2 infection and induce clinical manifestations similar to humans.
They subsequently challenged a total of ten groups of genetically distinct human ACE2-expressing mice with SARS-CoV-2 intranasally and monitored them for 21 days.
The comparative analysis of the mice revealed a wide variety of weight loss and survival profiles, with the two most sensitive strains showing 20% weight loss within 7 days post-infection, five strains showing 5-10% weight loss and 80% survival rate, and three strains showing gender-dependent susceptibility to lethal COVID-19. In two strains with gender-specific variations, male mice showed higher susceptibility to lethal disease. In another strain, a uniform susceptibility to lethal infection and sustained reduction in body weight was observed in female and male mice, respectively.
In highly sensitive strains, high titers of infectious SARS-CoV-2 were observed in the lungs and brain at day 3 and day 6 post-infection, respectively. In contrast, the most resistant mouse strain showed 150-fold reduced viral load in the lungs at day 3 post-infection compared to sensitive strains. A similar level of protection against the brain viral load was observed in the resistant strain.
In other resistant strains, lung viral loads were similar to that for sensitive strains at the initial phase of infection. However, relatively better control of viral replication and lower brain viral load were observed in resistant strains. Interestingly, mouse strains that showed gender-specific susceptibility to disease severity did not demonstrate any such variations in lung viral loads.
Regarding pathological changes, comparatively higher levels of lung pathologies were observed in resistant strains compared to that in sensitive strains. In all strains, viral RNA was detected only in type I and type II pneumocytes. Strikingly in one strain, microthrombi with widespread hemorrhage were observed in brain capillaries, which was associated with the presence of viral RNA.
Variation in immune response
The analysis of serum and respiratory cytokine and chemokine levels in infected mice revealed high expressions of interferon-alpha and proinflammatory cytokines and chemokines in respiratory samples at the initial infection phase (day 3 post-infection) were associated with better survival in both male and female mice belonging to the resistant strains. Moreover, resistant mice showed effective resolution of proinflammatory mediators along with high production of interferon-gamma at the later infection phase (day 6 post-infection). Collectively, these factors were found to associate with better clearance of the virus from the lungs.
In contrast, sensitive mice failed to induce an early inflammatory response and induced the production of proinflammatory mediators at the later phase of infection.
The study highlights the importance of early innate immune responses in determining COVID-19 severity. Moreover, the study indicates that variations in host genetics are associated with differential dynamics of type I interferon response and inflammation resolution, which collectively can modulate COVID-19 related morbidity and mortality.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.