Exploring the Role of Extracellular Vesicles in SARS-CoV-2 Reactivation and Transmission

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SARS-CoV-2, identified as the causative agent of the 2019–2021 viral pneumonia outbreak, led to a wide range of clinical manifestations known as COVID-19. The disease spectrum varied from asymptomatic or mild infections to severe respiratory illnesses, often progressing to respiratory and multiorgan failure. A key point to note is the increased risk of severe illness or complications in individuals with comorbidities, especially liver diseases.

Impact on Individuals with Liver Disease

Patients with chronic liver disease (CLD) were identified as being particularly vulnerable to severe COVID-19 complications. The virus, while primarily affecting the respiratory tract, showed potential implications beyond, with unexplored effects on other organs, including the liver.

Mysteries of SARS-CoV-2 Reactivation

Despite extensive research on clinical, epidemiological, and treatment aspects of COVID-19, the mechanisms of SARS-CoV-2 reactivation or recurrence remained largely unknown. Limitations in current detection methods, such as oropharyngeal or nasopharyngeal (NP) swab tests, often led to false negatives due to various factors like sampling sites and operator experience.

Insights from Hepatitis B Studies

Research on hepatitis B provided a breakthrough understanding that even in patients negative for hepatitis B virus (HBV) DNA, low amounts of HBV DNA could exist within extracellular vesicles (EVs). These EVs could transmit the virus to naïve hepatocytes, suggesting a parallel mechanism in SARS-CoV-2 transmission and persistence.

COVID-19 Recurrence and EVs

The reasons for COVID-19 recurrence were not well understood, particularly due to its unpredictable presentation irrespective of age, sex, or other physiological factors. The study hypothesized that EVs, including microvesicles (MVs) and exosomes, which are known to facilitate intercellular communication and transfer genetic materials in various viral infections, might also play a role in harboring and transmitting SARS-CoV-2.


TABLE 1 – COVID-19 Recurrence and Extracellular Vesicles: An Intriguing Puzzle

The unpredictable nature of COVID-19 recurrence, its seemingly random occurrence regardless of age, sex, or health status, has baffled researchers and continues to pose a significant public health challenge. While the primary focus has been on direct viral transmission, a growing body of evidence suggests that extracellular vesicles (EVs) might play a crucial role in facilitating recurrence.

EVs: Tiny Transporters with Big Potential:

EVs are microscopic membrane-enclosed packages released by cells. They contain various molecules, including proteins, RNA, and DNA, which can be transferred to recipient cells, influencing their function. In the context of viral infections, EVs have emerged as potential vehicles for viral transmission and immune modulation.

The Hypothesis:

This research proposes that EVs, specifically microvesicles (MVs) and exosomes, might play a key role in COVID-19 recurrence by:

  • Harboring SARS-CoV-2: Studies have shown the presence of viral RNA and even infectious virus particles within EVs isolated from COVID-19 patients. These EVs could act as a reservoir for the virus, enabling prolonged viral persistence even after initial clearance.
  • Facilitating viral transmission: EVs can efficiently evade immune detection and deliver their cargo, including viral components, to distant recipient cells. This could lead to the re-initiation of viral infection in previously cleared tissues, contributing to recurrence.
  • Modulating the immune response: EVs released by infected cells can suppress immune function, creating a window of opportunity for the virus to re-emerge. Additionally, EVs can trigger inflammatory responses, potentially contributing to the severity of recurrent cases.

Supporting Evidence:

  • Prolonged detection of viral RNA in EVs: Studies have shown the presence of SARS-CoV-2 RNA in EVs even after viral clearance from nasal swabs, suggesting a potential role in viral persistence.
  • Transmission of viral RNA via EVs: Research has demonstrated the ability of EVs isolated from COVID-19 patients to transfer viral RNA to recipient cells, potentially facilitating re-infection.
  • EVs and immune dysregulation: EVs released by infected cells can suppress immune function by inhibiting T cell activity and promoting the release of anti-inflammatory cytokines, potentially contributing to recurrence.

Challenges and Future Directions:

Despite the intriguing evidence, several challenges remain in fully understanding the role of EVs in COVID-19 recurrence. These include:

  • Distinguishing between active and inactive viral components in EVs: Differentiating between infectious virus particles and non-infectious viral RNA within EVs is crucial to accurately assess their role in transmission.
  • Identifying specific EV populations involved in recurrence: EVs are a heterogeneous population with diverse functions. Determining the specific EV sub-types involved in COVID-19 recurrence is essential for targeted therapeutic interventions.
  • Developing EV-based diagnostics and therapeutics: Novel methods for detecting and isolating EVs associated with COVID-19 recurrence could pave the way for improved diagnostics and therapeutic strategies.

Aim and Methodology of the Study

This study aimed to identify EV-associated SARS-CoV-2 RNAs in nasal swabs and plasma of COVID-19 patients, with or without CLD. Utilizing a centrifugation-based EV purification strategy, the study sought to characterize the relationship between SARS-CoV-2 RNAs and EVs, especially in cases where RNAs were undetectable in nasal swabs and plasma. Additionally, the study explored whether EV-associated SARS-CoV-2 could transmit infection to naïve cells in vitro.

Discussion

The findings presented in this study represent a significant advancement in our understanding of the behavior of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. This discussion will delve into the implications and significance of the study’s results, touching upon the persistence and likely recurrence of SARS-CoV-2 infection in extracellular vesicles (EVs), the potential for EVs to serve as a route of transmission, and the broader implications for COVID-19 management, especially in patients with chronic liver disease (CLD).

Persistence of SARS-CoV-2 in Extracellular Vesicles

The key novelty of this study lies in its groundbreaking discovery of SARS-CoV-2 RNAs within EVs collected from patients who had previously tested negative for the virus using conventional testing methods. This finding strongly suggests that the virus can persist within EVs even when it is undetectable in respiratory tract samples, thus raising the possibility of viral recurrence. Such persistence of SARS-CoV-2 RNA in EVs challenges our current understanding of the viral life cycle and its interactions with host cells.

One of the most intriguing aspects of this discovery is its potential impact on patients’ clinical outcomes. The presence of SARS-CoV-2 RNAs in EVs may serve as a marker for ongoing inflammation and could play a crucial role in understanding the clinical course of patients with undetectable viral loads. This information is especially relevant in the context of CLD patients, who are already at an increased risk of severe COVID-19. The study opens up new avenues for exploring the complex relationship between SARS-CoV-2, EVs, and the progression of the disease.

Relevance to COVID-19 Reactivation and Recurrence

The phenomenon of SARS-CoV-2 reactivation has been a subject of great concern since the early days of the pandemic. While the clinical characteristics of reactivation cases have been reported as similar to those without reactivation, the underlying mechanisms remain poorly understood. The study’s findings provide critical insights into the potential mechanisms behind reactivation and recurrence.

The fluctuating results of SARS-CoV-2 RNA tests in patients with undetectable viral loads may be attributed to the persistence of the virus in EVs. This persistence may also explain why some patients, even after recovering from COVID-19, continue to test positive. It is essential to recognize that patients in the convalescent phase may still carry infectious potential, thus necessitating further research to establish the contagious period of COVID-19 accurately.

Importantly, the presence of angiotensin-converting enzyme-2 (ACE-2), the cellular entry receptor for SARS-CoV-2, primarily in the lungs, suggests that viral load in respiratory specimens may vary considerably. False negatives in oropharyngeal or nasopharyngeal swab tests are possible due to multiple factors, such as sampling site, operator experience, and viral quantity. While bronchoalveolar lavage fluid specimens are considered more accurate, they pose higher exposure risks. The detection of SARS-CoV-2 RNAs in EVs offers a promising alternative for diagnosing COVID-19, potentially overcoming the limitations of current testing methods.

Implications for Diagnostic Advancements

The study’s findings highlight the urgent need for the development of rapid and precise diagnostic tests for SARS-CoV-2. Current testing turnaround times, often exceeding 24 hours, can delay the diagnosis and treatment of infected individuals. Moreover, serology tests, while rapid, may not be suitable for acute infection diagnosis due to the delayed antibody response.

The identification of SARS-CoV-2 RNAs within EVs may represent a breakthrough in diagnostic approaches. EV-associated RNA detection offers a potential solution to the challenges posed by existing testing methods. Since EVs are abundant in various body fluids and can be readily isolated, they provide an accessible and efficient means of detecting SARS-CoV-2, even in patients with negative RT-PCR results.

In Conclusion

While this study is not directly related to liver disease, its findings hold immense importance for the broader understanding of COVID-19 and its management. The identification of SARS-CoV-2 RNAs in EVs of patients with negative RT-PCR results sheds light on the persistence and likely recurrence of the virus. Moreover, it introduces the concept of EVs as potential carriers of the virus, offering a new route of transmission to explore.

As we continue to grapple with the complexities of the COVID-19 pandemic, this study provides valuable insights into the hidden facets of SARS-CoV-2 infection. It has the potential to shape future research directions, aid in the development of more accurate diagnostic tools, and ultimately contribute to improved patient care, particularly for those with comorbid conditions like chronic liver disease. The study underscores the urgency of further investigations into SARS-CoV-2 persistence, recurrence, and its interactions with extracellular vesicles.


reference link : https://www.sciencedirect.com/science/article/pii/S2542568423000491

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