COVID-19 News: Study Shows That SARS-CoV-2 ‘Disarms’ Innate Immunity In ‘Recovered’ Individuals To Pave The Path For Viral Persistence In Lungs!

COVID-19 News: As the world grapples with the ongoing challenges posed by the COVID-19 pandemic, new revelations about the persistence of SARS-CoV-2, the virus responsible for COVID-19, shed light on the intricacies of the human immune response. A recent study conducted by researchers from the Institut Pasteur, specializing in HIV, in collaboration with the French public research institute CEA, has unveiled a startling discovery - the SARS-CoV-2 virus persists in the lungs of recovered individuals for up to 18 months after infection, challenging the notion that recovery implies the complete eradication of the virus from the body!


 
Persistence in the Lungs
Typically, one to two weeks after contracting COVID-19, SARS-CoV-2 becomes undetectable in the upper respiratory tract. However, this does not necessarily indicate its absence from the body. The study covered in this COVID-19 News report, focused on lung cells in a preclinical model of non-human primates to investigate the longevity of SARS-CoV-2 presence. Astonishingly, the results revealed the persistence of the virus in the lungs of certain individuals for an extended period, ranging from 6 to 18 months post-infection!
 
The Nature of Viral Reservoirs
The concept of viral reservoirs, where viruses linger discreetly after causing an initial infection, is not new. HIV, for instance, can remain latent in specific immune cells, reactivating unpredictably. The researchers hypothesized a similar scenario for SARS-CoV-2, and their findings in the non-human primate model substantiate this hypothesis. Dr Michaela Müller-Trutwin, Head of the Institut Pasteur's HIV, Inflammation, and Persistence Unit, remarked, "We observed that inflammation persisted for long periods in primates that had been infected by SARS-CoV-2. We therefore suspected that it could be due to the presence of the virus in the body."
 
Surprising Discoveries in the Lungs
The study yielded unexpected findings - even when conventional PCR tests returned negative results and the virus was undetectable in the upper respiratory tract or blood, viruses were discovered in certain immune cells, specifically alveolar macrophages, within the lungs. Dr Nicolas Huot, the first author of the study, emphasized the surprise, stating, "What's more, we cultured these viruses and were able to observe, using the tools we developed to study HIV, that they were still capable of replicating."
 
Role of Innate Immunity
To unravel the mechanisms behind this prolonged viral presence, the researchers turned their attention to innate immunity, the body's initial defense against pathogens. Natural killer (NK) cells, a crucial component of innate immunity, play a significant role in controlling viral infections. The study found that in some individuals, macrophages infected with SARS-CoV-2 became resistant to destruction by NK cells. In contrast, adaptive NK cells in other individuals successfully adapted to the infection, destroying resistant cells, particularly macrophages.
 
Understanding the Immu ne Response
The cellular response of innate immunity, particularly the role of NK cells, had been relatively understudied in the context of SARS-CoV-2 infections. Dr Michaela Müller-Trutwin highlighted the importance of NK cells, stating, "The cellular response of innate immunity, which is the body's first line of defense, has been little studied in SARS-CoV-2 infections until now. Yet it has long been known that NK cells play an important role in controlling viral infections." The study illuminated a potential link between the levels of persistent SARS-CoV-2 and the presence or absence of adaptive NK cells.
 
Interplay Between NK Cells and Macrophages
The research elucidated a nuanced interplay between NK cells and macrophages that regulated the persistence of SARS-CoV-2 in macrophages. The critical factor was interferon-gamma (IFN-γ), a cytokine involved in antiviral responses. The study found that IFN-γ inhibited the replication of SARS-CoV-2 in bronchioalveolar lavage (BAL) macrophages. The strongest production of IFN-γ occurred in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer cells. However, impaired IFN-γ production was observed in NK cells from macaques with persisting virus.
 
Variability in Immune Response
The study unveiled a variable immune response among individuals, with some exhibiting adaptive NK cell production, associated with lower levels of persistent virus. In contrast, individuals with higher levels of virus not only lacked adaptive NK cells but also demonstrated a reduction in NK cell activity. This variability in innate immunity's effectiveness hinted at potential connections to the phenomenon of long COVID, prompting further investigation into a cohort infected at the start of the pandemic.
 
Viral Persistence Mechanisms
The researchers discovered that the persistence of SARS-CoV-2 in lung alveolar macrophages was controlled by IFN-γ and NK cells. The study delved into the molecular mechanisms involved, shedding light on the role of major histocompatibility complex (MHC)-E on BAL macrophages. IFN-γ not only inhibited viral replication but also enhanced the expression of MHC-E, potentially inhibiting NK cell-mediated killing.
 
Insights from Non-Human Primate Models
Non-human primate models played a crucial role in unraveling the complexities of SARS-CoV-2 persistence and the immune response. Cynomolgus macaques provided a valuable tool for studying immune cell functioning and responses in tissues, offering insights into human infectious diseases. The study used a comprehensive approach, including multiparameter flow cytometry, to analyze BALF cells, revealing alterations in macrophage phenotype and lymphocyte frequencies in infected macaques.
 
Long-Term Effects on Macrophages
The study explored the long-term effects of SARS-CoV-2 on macrophages (Mac) within the bronchoalveolar lavage fluid (BALF). Mac, comprising a significant portion of the lung's total leukocyte population, responded to microbial threats but exhibited dysregulation during SARS-CoV-2 infection. Long-term alterations in Mac phenotype, marked by increased expression of CD206, CD4, CD11c, MHC-E, and IL-10, were observed. These changes indicated an alternative activation of alveolar Mac, potentially contributing to lung contusion and pneumonia.
 
Viral Replication in Macrophages
Detection of replication-competent SARS-CoV-2 in BALF Mac was a groundbreaking revelation. The study utilized reverse transcription polymerase chain reaction (RT–PCR) to identify viral RNA in BALF cells, grouping macaques based on viral load levels. The presence of viral antigens in BALF Mac, confirmed through the detection of spike protein, indicated ongoing viral replication. Confocal images revealed the existence of double-stranded RNA and nonstructural protein 3 (NSP3) within BALF Mac, suggesting viral replication through cell-to-cell propagation.
 
Transcriptomic Analysis of Macrophages
In-depth transcriptomic analysis of cultured BALF Macs exposed the molecular changes induced by SARS-CoV-2 replication. Increased expression of fibronectin (FN1), S100A8/S100A9 (calprotectin), and CD1b, a nonpolymorphic MHC class I-like glycoprotein, hinted at sustained immune activation and chronic inflammation. Notably, the study emphasized the importance of investigating these changes in the context of potential long COVID manifestations, expanding the scope beyond acute infection.
 
IFN-γ's Dual Role in Viral Persistence
IFN-γ, a pivotal immunoregulatory cytokine, demonstrated a dual role in the context of SARS-CoV-2 infection. On one hand, it exhibited antiviral properties by inhibiting viral replication in BALF Mac. On the other hand, IFN-γ induced the upregulation of MHC-E on infected cells, potentially shielding them from NK cell-mediated lysis. This dual impact underscored the complexity of the immune response against SARS-CoV-2, where a crucial cytokine simultaneously controlled viral replication and contributed to the persistence of infected cells.
 
SARS-CoV-2 Spike Protein's Modulation of Immune Response
The study highlighted the role of the SARS-CoV-2 spike protein in modulating NK cell function and immune evasion. Peptides derived from the spike protein, such as V3-11, were identified as binders to MHC-E, inhibiting NK cell degranulation activity. Intriguingly, the extent of inhibition correlated with viral load and the presence of spike protein in infected Mac. This observation suggested a dynamic interaction between the viral protein and immune response, influencing the persistence of SARS-CoV-2.
 
Conclusion: Unraveling the Tapestry of SARS-CoV-2 Persistence
In conclusion, the study offers a comprehensive exploration of the complex interplay between SARS-CoV-2, innate immunity, and the lungs. The revelation of viral persistence in recovered individuals opens new avenues for understanding the long-term consequences of COVID-19. The dynamic interactions between viral reservoirs, alveolar macrophages, NK cells, and key cytokines like IFN-γ provide valuable insights into the mechanisms underlying persistent SARS-CoV-2 infections. As the scientific community delves deeper into the intricacies of viral persistence, these findings pave the way for future research aiming to unravel the mysteries of long COVID and inform the development of targeted therapeutic interventions.
 
The study findings were published in the peer reviewed journal: Nature Immunology.
https://www.nature.com/articles/s41590-023-01661-4
 
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