COVID-19: CD8 T cells are very important in protecting the brain after infection of nasal tissue


Researchers at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health, have identified a specific, front-line defense that limits the infection to the olfactory bulb and protects the neurons of the olfactory bulb from damage due to the infection.

Neurons in the nose respond to inhaled odors and send this information to a region of the brain referred to as the olfactory bulb.

Although the location of nasal neurons and their exposure to the outside environment make them an easy target for infection by airborne viruses, viral respiratory infections rarely make their way from the olfactory bulb to the rest of the brain, where they could cause potentially fatal encephalitis. The study was published in Science Immunology.

Taking advantage of special viruses that can be tracked with fluorescent microscopy, the researchers led by Dorian McGavern, Ph.D., senior investigator at NINDS, found that a viral infection that started in the nose was halted right before it could spread from the olfactory bulb to the rest of the central nervous system.

“Airborne viruses challenge our immune system all the time, but rarely do we see viral infections leading to neurological conditions,” said Dr. McGavern.

“This means that the immune system within this area has to be remarkably good at protecting the brain.”

Additional experiments showed that microglia, immune cells within the central nervous system, took on an underappreciated role of helping the immune system recognize the virus and did so in a way that limited the damage to neurons themselves. This sparing of neurons is critical, because unlike cells in most other tissues, most neuronal populations do not come back.

Because of this, the central nervous system has evolved to include several defense mechanisms designed to keep pathogens out. However, when airborne viruses are inhaled, they travel through the nasal passages and interact with a tissue called the olfactory epithelium, which is responsible for our sense of smell. Neurons at the edge of the olfactory system extend small projections through the bone lining the nasal cavity.

These projections enter the brain, giving it access to odors present in the air. Neurons in the olfactory epithelium also offer an easy way for viruses to bypass traditional central nervous system barriers by providing a direct a pathway to the brain.

“If a virus infects the processes of neurons that dangle within the airway, there is a chance for this virus to enter the brain, and ultimately cause encephalitis or meningitis,” said Dr. McGavern.

“We are interested in understanding immune responses that develop at the interface between nasal olfactory neurons, which end in the olfactory bulb, and the rest of the brain.”

Dr. McGavern’s team was able to show that CD8 T cells, which are part of the immune system responsible for controlling viruses, are very important in protecting the brain after infection of nasal tissue. Using advanced microscopy, his group watched in real time how CD8 T cells protected the brain from a nasal virus infection.

Interestingly, the CD8 T cells did not appear to interact directly with neurons, the predominately infected cell population. They instead engaged microglia, which are central nervous system immune cells that act a bit like garbage collectors by clearing cellular debris and dead cell material.

Image of a brain scan
When virus (labeled in green) enters the nasal passages, its spread is abruptly halted just before entering the CNS (blue oval structures at the top of the image). McGavern lab

When a viral infection occurs, the microglia appear to take up virus material from the surrounding environment and present it to the immune system as though they had become infected.

In this way, infected olfactory neurons can “hand off” virus particles to microglia, which were then detected by the T cells.

The T cells then respond by releasing antiviral molecules that clear the virus from neurons in a way that does not kill the cells. Because microglia are a renewable cell type, this type of interaction makes sense from an evolutionary standpoint.

“The immune system has developed strategies to favor the preservation of neurons at all costs,” said Dr. McGavern. “Here, we show that microglia can ‘take the blow’ from neurons by engaging T cells, which then allows the antiviral program to play out.”

Considerable attention has been paid to respiratory viral infections of late due to the current COVID-19 pandemic.

Dr. McGavern noted that, while that virus was not studied in these experiments, some of the symptoms it produces suggest that the same mechanism described here could be in play.

“One of the interesting symptoms associated with infection by novel coronavirus is that many people lose their sense of smell and taste. This suggests that the virus is not only a respiratory pathogen, but likely targets or disrupts olfactory sensory neurons as well.”

It is important to note that widespread infection of the olfactory sensory neurons, whether by the novel coronavirus, the virus used in this study, or any other similar virus, will likely disrupt our sense of smell. However, unlike other neurons in the central nervous system, these sensory neurons that begin in the nose and end in the brain are capable of regenerating after an infection is cleared.

“The immune response we describe does not protect olfactory sensory neurons nor the sense of smell,” explained Dr. McGavern.

“This is not necessarily a long-term issue, because those sensory neurons can be replaced once the virus is dealt with. What is critical is to protect the brain and central nervous system from encephalitis or meningitis—our sense of smell can often be repaired over time.”

Dr. McGavern continued by saying that given the importance of microglia in stimulating the antiviral response, factors that can lead to their depletion or loss of function could increase susceptibility to central nervous system infection.

COVID-19 infection & the immune response it elicits
Immune response against the novel coronavirus

The current understanding of how a dysregulated immune response that causes lung immunopathology would lead to deleterious clinical manifestations after pathogenic hCoV infections was reported in prior studies.

As early as 2017, Channappanavar and Perlman declared that recent identification of SARS-like coronaviruses in bats and MERS-CoV in domesticated camels makes it likely that these viruses will continue to cross species barriers and cause additional outbreaks in human populations [11].

These highly pathogenic hCoVs cause a wide spectrum of clinical manifestations in humans, with a large fraction of patients developing short period of moderate clinical illness and a small but a substantial number of patients experiencing severe disease characterized by acute lung inflammation and acute respiratory disease [11].

There are certain inflammatory responses that may be conducive to cancer. IFN-α/β or inflammatory monocyte-macrophage-derived pro-inflammatory cytokines sensitized T cells to undergo apoptosis, further impeding virus clearance [11].

The loss of TIR-domain-containing adapter-inducing IFN-β (TRIF), an adapter molecule for TLR-3 and TLR-4 signaling, resulted in a distinct inflammatory signature characterized by neutrophil and other inflammatory cell infiltration [11].

A dysregulated immune response to SARS-CoV in TRIF-deficient mice was associated with aberrant antiviral IFN (IFN-α and IFN-β), pro-inflammatory cytokine and chemokine (IL-6, TNF, IFN-γ and monocyte chemoattractant CCL5), and interferon-stimulated gene (RSAD2, IFIT1 and CXCL10) responses, another possible indicator of cancer risk [11].

Multiple structural and nonstructural proteins of SARS-CoV antagonize interferon responses [5]. Very early after infection, hCoV reach high titers and sequester multiple proteins that inhibit the interferon response, suggesting that immune response delay or evasion may be the result of early antagonism of the interferon [11]. A dysfunctionally regulated inflammatory response and T-cell apoptotic sensitization is also further orchestrated by the delayed interferon signaling [11].

Some consequences of cytokine storm and immunopathology are epithelial and endothelial cell apoptosis and vascular leakage, suboptimal T-cell response, in other words. CoV-specific T cells are crucial for virus clearance and limit further damage to the host. Additionally, T-cell responses also dampen overactive innate immune responses [11].

Exuberant inflammatory responses caused by pathogenic hCoV diminish the T-cell response, in the case of SARS CoV infection via TNF-mediated T-cell apoptosis, thus resulting in uncontrolled inflammatory response; accumulation of alternatively activated macrophages and altered tissue homeostasis; and acute respiratory distress syndrome [11].

Figure 4 demonstrates the enormous immune response against the novel coronavirus [12]. The innate immune response and adaptive immunity have distinct responses to coronaviruses infection [12].

The SARS-Cov-2 (CoV) infects macrophages, and then macrophages present CoV antigens to T cells and this process leads to T-cell activation and differentiation, including the production of cytokines associated with the different T-cell subsets (i.e., T helper cells), followed by a massive release of cytokines for immune response amplification [12].

The continued production of these mediators due to viral persistence has a negative effect on natural killer cells and CD8+ T-cell activation, and CD8+ T cells produce very effective mediators to clear CoV [6].

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Figure 4.
COVID-19 infection and the immune response.
Activated signaling pathways such as JAK–STAT and MAPK, cytokine storm, T-cell depletion, humoral responses and high levels of inflammation may predispose patients infected with novel coronavirus to cancer.
Reproduced with permission from [12].

The attachment of CoV to DPP4R on the host cell through S protein leads to the appearance of genomic RNA in the cytoplasm. An immune response to dsRNA that results can be partially generated during CoV replication.

TLR-3 sensitized by dsRNA leads to cascades of signaling pathways (IRFs and NF-κB activation, respectively) which are activated to produce type I interferons and pro-inflammatory cytokines [12].

The production of type I interferons is important to enhance the release of antiviral proteins for the protection of uninfected cells. Sometimes, accessory proteins of CoV can interfere with TLR-3 signaling and bind the dsRNA of CoV during replication to prevent TLR-3 activation and evade the immune response [12].

TLR-4 might recognize S protein and lead to the activation of pro-inflammatory cytokines through the MyD88-dependent signaling pathway. Virus–cell interactions lead to the strong production of immune mediators [6]. The secretion of large quantities of chemokines and cytokines (IL-1, IL-6, IL-8, IL-21, TNF-β and MCP-1) is promoted in infected cells in response to CoV infection. These chemokines and cytokines, in turn, recruit lymphocytes and leukocytes to the site of infection [12].


6. Advisory Board: it’s not just lungs: COVID-19 may damage the heart, brain, and kidneys (2020).

11. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 39(5), 529–539 (2017). [PMC free article] [PubMed] [Google Scholar]• An early article on the molecular responses to coronavirus infection and possibility of pandemics.

12. Li G, Fan Y, Lai Y. et al. Coronavirus infections and immune responses. J. Med. Virol. 92(4), 424–432 (2020). [PMC free article] [PubMed] [Google Scholar]•• An excellent overview with graphics on the immune-mediated responses to coronavirus.

More information: Moseman, EA et al. T cell engagement of cross-presenting microglia protects the brain from nasal virus infection. Science Immunology. June 5, 2020. DOI: 10.1126/sciimmunol.abb1817



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