The Complex Interplay Between SARS-CoV-2 Infection, Lung Cancer, and Toll-Like Receptors


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a profound impact on global health since its emergence in late 2019. This novel coronavirus is responsible for the COVID-19 pandemic, which has led to millions of infections and deaths worldwide.

While the virus primarily targets the respiratory system, affecting individuals in various ways, mounting evidence suggests that SARS-CoV-2 infection can have a particularly severe impact on patients with underlying health conditions, including cancer [1].

Lung cancer, in particular, has emerged as a significant concern in the context of COVID-19. Patients with lung cancer appear to manifest severe COVID-19 symptoms at a disproportionately higher rate, leading to increased hospitalization and mortality [2].

The reasons behind this alarming trend have been a subject of intense research. One intriguing aspect is the role of the SARS-CoV-2 Spike (S) protein in inducing hyper-inflammation, especially through the toll-like receptor (TLR) pathways [3].

However, the molecular and cellular mechanisms underlying the relationship between SARS-CoV-2 infection and the severity of lung cancer remain elusive.

Understanding Lung Cancer and Its Vulnerability

Lung cancer, one of the leading causes of cancer-related deaths worldwide, manifests primarily in the lungs, often as malignant tumors. These tumors can interfere with normal lung function, leading to respiratory problems. Lung cancer patients frequently experience symptoms such as coughing, shortness of breath, and chest pain, which are exacerbated when the virus attacks the respiratory system.

Impact on Susceptibility

  • Immunosuppression: Lung cancer patients typically exhibit weakened immune systems. Cancer itself, along with various treatments like chemotherapy and radiation therapy, can suppress the immune response. This immunosuppression can make them more susceptible to SARS-CoV-2 infection.
  • Age: Advanced age is a significant risk factor for severe COVID-19. Lung cancer is most common in older individuals, making this group particularly vulnerable to both lung cancer and severe COVID-19.
  • Comorbidities: Many lung cancer patients have comorbid conditions, such as heart disease or diabetes, which can further increase their susceptibility to severe COVID-19.

Impact on Severity

  • Respiratory Compromise: Lung cancer patients already have compromised lung function due to the presence of tumors and inflammation. When SARS-CoV-2 infects the respiratory system, it can lead to a double burden on the lungs, making it even harder for patients to breathe and oxygenate their bodies.
  • Cytokine Storm: In severe COVID-19 cases, the immune system can go into overdrive, releasing excessive amounts of cytokines. This “cytokine storm” can cause widespread inflammation and organ damage. Lung cancer patients, with their already weakened immune systems, may be less equipped to handle this immune response, leading to more severe outcomes.
  • Treatment Complications: Lung cancer patients often receive treatments that can weaken their immune systems further. Chemotherapy, for example, can reduce the number of white blood cells, which are crucial for fighting off infections. This can complicate the management of SARS-CoV-2 infection.

This article delves into a comprehensive study that aims to shed light on the intricate connection between SARS-CoV-2 susceptibility, severity in lung cancer patients, and the involvement of TLR1/2 or TLR2/6 signaling pathways.

Methods and Data Analysis

To investigate the association between SARS-CoV-2 susceptibility and lung cancer, the study utilized microarray data from 42 non-small cell lung cancer (NSCLC) patients. The researchers analyzed differences in the expression of angiotensin-converting enzyme 2 (ACE2) and TLR2 (∆ACE2 and ∆TLR2, respectively) between lung tumor tissues and matched normal lung tissues.

Based on these differences, two groups were selected: 11 patients with upregulated ACE2 and TLR2 and 11 with downregulated ACE2 and TLR2.

Gene set enrichment analysis (GSEA) was performed to determine the statistical association of ACE2 and TLR2 expression with gene sets related to cancer, SARS-CoV-2 infection, and TLR signaling.

The results revealed significant enrichment of cancer-related gene sets in lung tumor tissues with upregulated ACE2 and TLR2. Moreover, gene sets associated with SARS-CoV-2 infection and the TLR signaling pathway were also significantly enriched in these tissues.

This enrichment extended to downstream signaling targets and pathways, such as the NF-κB pathway, interferon-α/β signaling, and cytokine pathways. The findings suggest that increased ACE2 and TLR2 expression in lung cancer tissues is associated with cancer progression, SARS-CoV-2 infection, and inflammatory responses.

SARS-CoV-2 Spike Protein and Lung Cancer Progression

Given that the SARS-CoV-2 S protein can induce inflammation through TLR1/2 or TLR2/6-dependent activation of the NF-κB pathway, the study explored whether this viral protein could promote lung cancer progression. They conducted experiments using lung cancer cell lines (A549 and H1299) and found that treatment with the SARS-CoV-2 S protein or TLR agonists (Pam3CSK4 and FSL-1) significantly enhanced migration, invasion, colony formation, and cell proliferation. These effects were accompanied by increased phosphorylation of key signaling molecules and the production of inflammatory cytokines.

The results suggest that the SARS-CoV-2 S protein can directly induce lung cancer progression by activating the NF-κB pathway via TLR1/2 and TLR2/6. However, further investigation is needed to fully understand the underlying mechanisms.

TLR2 and Lung Cancer Progression

To directly assess the role of TLR2 in lung cancer progression induced by the SARS-CoV-2 S protein, TLR2-knockout (KO) lung cancer cells were generated using CRISPR-Cas9 gene editing. The study found that TLR2-KO cells exhibited markedly attenuated migration, invasion, and cytokine production in response to SARS-CoV-2 S protein and TLR agonists. This suggests that TLR2 plays a critical role in mediating the effects of the virus on lung cancer progression.


In conclusion, this study provides valuable insights into how SARS-CoV-2 infection impacts susceptibility and severity in lung cancer patients. Patients with upregulated ACE2, TLR1, TLR2, TLR6, and TMPRSS2 appear to be more susceptible to SARS-CoV-2 infection, leading to more severe outcomes. Furthermore, the virus promotes cancer progression through TLR2-dependent activation of NF-κB.

However, it’s important to note that the role of TLR2 in lung tumor progression is complex, as it can have both pro-tumor and anti-tumor effects in different stages of lung cancer. Further research is required to elucidate the precise molecular and cellular mechanisms involved. Nevertheless, this study contributes significantly to our understanding of how SARS-CoV-2 infection influences lung cancer progression, which may aid in the development of targeted therapies and better management of COVID-19 in patients with lung cancer.

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