ACE2-Independent Infection and Immune Evasion by SARS-CoV-2

February 20, 2024

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SARS-CoV-2, the virus that causes COVID-19, has infected millions of people worldwide since first emerging in 2019. A key feature of SARS-CoV-2 that enables its easy spread is its ability to evade and dysregulate immune responses. Understanding how this immune subversion occurs has important implications for developing effective treatments and vaccines. An emerging area of research is the discovery that SARS-CoV-2 can infect T lymphocytes independently of the ACE2 receptor, allowing unique forms of immune modulation and evasion.

ACE2-Mediated Infection

SARS-CoV-2 gains entry into host cells primarily through the angiotensin-converting enzyme 2 (ACE2) receptor. The viral spike protein binds to ACE2, triggering a conformational change that allows the virus to fuse with and enter the cell. ACE2 is expressed in tissues like the lungs, heart, kidneys, and intestines – explaining the variety of symptoms caused by COVID-19.

The type 2 transmembrane serine protease TMPRSS2 is also involved, priming the spike protein to enhance ACE2 binding affinity. Together, ACE2 and TMPRSS2 comprise the main cellular vulnerability exploited by SARS-CoV-2 to infect cells and spread through the body.

Key cellular targets of SARS-CoV-2 infection via the ACE2 receptor include:

  • Alveolar epithelial cells
  • Vascular endothelium
  • Alveolar macrophages
  • Cardiomyocytes

ACE2 Expression on Lymphocytes

Lymphocytes, including T cells and B cells, are key orchestrators and effectors of anti-viral immunity. However, ACE2 is not highly expressed on most immune cell populations. The low abundance of ACE2 on lymphocytes suggests that the adaptive immune system should remain mostly functional against SARS-CoV-2.

Yet the hallmark of severe COVID-19 is the presence of lymphopenia, impaired lymphocyte function, and cytokine storm – pointing to significant immune dysregulation by the virus. This poses an immunological paradox regarding lymphocyte targeting by SARS-CoV-2 that is independent of ACE2.

Emerging research indicates that SARS-CoV-2 can directly infect T cells via cell surface receptors other than ACE2 or through cell-cell contact. This allows unique mechanisms of immune attack and evasion beyond just virus sensing and cytokine signaling dysfunction.

ACE2-Independent Infection of T Lymphocytes

In 2022, scientists discovered that SARS-CoV-2 efficiently infects activated CD4+ T helper cells without needing ACE2 or TMPRSS2. Upon gaining entry into T cells, active viral replication occurs with production of genomic RNA, subgenomic RNAs, and viral proteins.

Mechanisms of ACE2-Independent T Cell Infection

The exact mechanisms of ACE2-independent lymphocyte infection are still under investigation but may involve:

  • Alternative cell receptors – proteins like CD147, CD209, and CLEC5A can bind the SARS-CoV-2 spike protein and facilitate viral entry.
  • Cell-cell fusion – SARS-CoV-2 expressed on an infected cell can fuse with receptor-negative lymphocytes via syncytia/nanotube formation.
  • Antibody-dependent enhancement – anti-SARS-CoV-2 antibodies opsonize virus particles and direct their binding/uptake into lymphocytes via Fc receptors.

Of these, cell-cell viral transfer represents an efficient mode of lymphocyte infection and demise. Syncytia formation between infected cells and lymphocytes produces multinucleated giant cells that ultimately burst and die. This cytopathic effect allows production of high viral loads while destroying anti-viral lymphocytes.

Consequences of Lymphocyte Infection

SARS-CoV-2 infection of T cells and other lymphocytes results in several immunopathological consequences:

  • Lymphopenia – Direct viral killing of lymphocytes causes the hallmark lymphopenia of severe COVID-19.
  • Loss of immune memory – Infection of memory T and B cells destroys recall responses to other pathogens.
  • Weakened immunity – With fewer lymphocytes, immune control of SARS-CoV-2 itself is reduced.
  • Cellular exhaustion – Persisting viral antigen drives overstimulation and exhaustion of virus-specific T cells.

Through these effects, ACE2-independent infection of lymphocytes complements the immune subversion achieved by SARS-CoV-2 via cytokine signaling disturbances and hyperinflammation.

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Evasion of Immune Defenses by SARS-CoV-2

In addition to direct infection, SARS-CoV-2 has evolved an impressive array of strategies to manipulate innate and adaptive immunity. These mechanisms of immune escape help explain why COVID-19 can progress to severe and fatal disease.

Avoiding Innate Immune Detection

While the innate immune system deploys early warning systems to sense invading viruses, SARS-CoV-2 manages to remain stealthy in several ways:

  • The proofreading exoribonuclease (ExoN) activity of its nsp14 protein caps viral RNA to hide pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs).
  • Nucleocapsid binding to viral RNA also helps mask these PAMPs from detection by RIG-I and MDA5.
  • Production of ornithine decarboxylase degrades MAVS adaptor proteins required for activating anti-viral transcription factors like IRF3 and NF-kB.
  • Nsp1, Nsp3, and N protein of SARS-CoV-2 also inhibit mRNA transcription of anti-viral cytokines and interferons by the host cell.

As a result, SARS-CoV-2 replication can proceed relatively undetected, avoiding immediate innate immune attack.

Cell-Cell Spread Through Tunneling Nanotubes

An ingenious mechanism for evading neutralizing antibodies is the ability of SARS-CoV-2 to spread directly between immune cells via cytoplasmic bridges called tunneling nanotubes (TNTs). TNT connections between infected and uninfected cells allow cell-cell transmission of whole virions or viral proteins without exposure to extracellular fluids.

This protected mode of cell-cell viral transfer not only promotes infection but also allows SARS-CoV-2 to hide from humoral immunity mediators like neutralizing antibodies. Spreading the infection via TNTs to symptoms of lymphopenia and T cell exhaustion. through cell-cell transmission.

Molecular Mimicry

A key tactic in all microbial pathogen defense strategy is to mimic host proteins as a form of camouflage against immune attack. Often small viral peptide sequences resemble motifs on human proteins just enough to trick the immune system into standing down.

The spike and nucleocapsid proteins of SARS-CoV-2 similarly share short linear peptide sequences with human proteins that regulate complement or leukocyte trafficking. By mimicking these indispensable host proteins, SARS-CoV-2 masks itself from immune elimination.

This molecular mimicry can also result in production of autoantibodies against host tissues as collateral damage of the anti-viral immune response. The resulting organ pathology may be responsible for some of the extrapulmonary effects seen in COVID-19.

Blunting Interferon Responses

Release of type I interferons like IFNα/β represents a crucial first line of defense against viral infections. However, SARS-CoV-2 has evolved ways to selectively dampen cellular interferon production and downstream JAK-STAT signaling:

  • Nsp1, Orf6, and N proteins inhibit activation of key transcription factors like IRF3 that normally induce IFN transcription.
  • The spike protein decreases expression of IFNAR1 receptor subunits to reduce interferon responsiveness.
  • Post-entry inhibition of SUMOylation by SARS-CoV-2 papain-like protease (PLpro) prevents nuclear translocation of transcription factors needed for stimulating interferon-stimulated genes (ISGs).

Through these mechanisms, SARS-CoV-2 evades the earliest interferon-mediated antiviral response that normally controls viral replication until adaptive immunity can be mobilized.

Key Knowledge Gaps

While emerging data paints a picture of how SARS-CoV-2 evades immunity through ACE2-dependent and independent mechanisms, key questions remain:

  • What specific cellular receptors allow ACE2-independent infection of lymphocytes?
  • How exactly do SARS-CoV-2-infected lymphocytes interact with and modulate other immune cells?
  • Would blocking ACE2-independent lymphocyte infection restore protective immunity against COVID-19?

Ongoing studies to clarify these issues may reveal new therapeutic opportunities against this formidable pathogen.

Conclusions and Implications

The COVID-19 pandemic has revealed SARS-CoV-2 to be a remarkably adept viral adversary that manages to circumvent innate and adaptive immune defenses through both direct and indirect mechanisms. Understanding details of SARS-CoV-2 immune evasion can lead to more strategic deployment of antiviral drugs, neutralizing antibodies, and vaccines.

An emerging concept is that SARS-CoV-2 can directly infect T lymphocytes independently of ACE2 through alternative receptors and cell-cell transfer. This allows unique forms of immune subversion including destruction of lymphocytes, loss of immunological memory, and induction of cell exhaustion phenotypes.

Therapies that protect lymphocytes from infection, or modulate their dysregulated signaling, may provide clinical benefits – especially in high-risk patients prone to immune pathogenesis. As virologists race to find new antiviral targets, outsmarting SARS-CoV-2 at the level of host immunity may also tilt the balance in favor of human health.

Frequently Asked Questions

What is ACE2-independent infection of lymphocytes?

ACE2-independent infection refers to SARS-CoV-2’s ability to infect T cells and other lymphocytes without needing the ACE2 receptor. Instead, the virus uses alternative cell surface proteins like CD147 or enters cells via direct contact with infected cells. This allows infection of lymphocytes not expressing ACE2.

How does SARS-CoV-2 evade the immune system?

SARS-CoV-2 evades immunity using tactics like hiding viral PAMPs from innate sensors, spreading via nanotubes to avoid antibodies, molecular mimicry of host proteins, inhibiting interferon responses, and directly infecting and killing lymphocytes. These mechanisms of immune escape enable high viral loads and disease progression.

Can SARS-CoV-2 infect T cells?

Yes, SARS-CoV-2 can directly infect T lymphocytes by mechanisms independent of ACE2 and TMPRSS2. CD4+ T cells appear particularly vulnerable, with active viral replication occurring after cell entry. T cell infection causes lymphopenia, loss of recall immunity, and cell exhaustion – contributing to COVID-19 severity.

What causes lymphopenia and cytokine storm in COVID-19?

Severe COVID-19 is characterized by lymphopenia and cytokine storm. Lymphopenia arises from direct viral destruction of T and B cells as well as excessive lymphocyte activation and exhaustion. Cytokine storm results from widespread immune cell dysfunction and tissue damage, marked by heightened inflammation. SARS-CoV-2 evasion of immunity facilitates these outcomes.

What are the clinical implications of SARS-CoV-2 immune evasion?

The ability of SARS-CoV-2 to bypass immune control mechanisms helps explain poor clinical outcomes in a subset of patients. Therapies that help detect viral infection, protect lymphocytes, enhance interferon responses, modulate inflammation, and stimulate protective immunity may have benefit in severe disease. Understanding viral immune evasion provides clues for more targeted COVID-19 management.

Key Takeaways

  • SARS-CoV-2 uses ACE2 for infection but can also enter lymphocytes independently via alternate receptors.
  • Infection of T cells causes lymphopenia, weakened anti-viral immunity, and loss of immunologic memory.
  • The virus utilizes multiple tactics to hide from innate immune sensors and evade antibody neutralization.
  • Poor interferon responses and molecular mimicry also enable SARS-CoV-2 persistence.
  • Blocking evasion pathways and protecting lymphocytes represent therapeutic opportunities.


  1. Shen, X. R., et al (2022). ACE2-independent infection of T lymphocytes by SARS-CoV-2. Cellular & Molecular Immunology.
  2. Kuklina, E.M. (2022). T Lymphocytes as Targets for SARS-CoV-2. Front Immunol 13: 897484.
  3. Nomaguchi, M. et al (2020). Molecular basis of SARS-CoV-2 cell entry and lack of inhibition by clinically available antiviral drugs. iScience, 23(12), 101912.
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