The scientists from University College London and the University of Cambridge uncovered critical aspects of how the body interacts with the SARS-CoV-2 virus at different stages of infection. To understand how the virus affects cells, 16 young volunteers without prior antibodies were deliberately infected with SARS-CoV-2. The volunteers were thoroughly screened beforehand to minimize the risk of severe illness. A minimal dose of the virus was administered to reduce risks and closely mimic real-world exposure conditions.
After infection, the researchers studied the participants’ immune responses by analyzing blood and nasopharyngeal cells. As in real-world scenarios, the administered viral dose caused infection in some participants, while others did not experience significant infection:
- Six participants developed a persistent infection, which was confirmed by PCR tests and symptoms.
- Three participants intermittently tested positive on PCR, indicating a transient infection—a temporary state where the virus is detectable in the body only briefly and does not lead to a full-blown infection or illness. In the context of COVID-19, this suggests that the virus is present early on, but the immune system quickly neutralizes it, preventing a full infection.
- Seven participants remained PCR-negative, meaning their immune systems prevented the infection from developing. These cases were termed abortive infections, where early immune responses were observed, but antibodies were not produced.
Molecular Responses Precede Symptoms
The researchers investigated how immune responses correlate with COVID-19 symptoms. In participants with persistent infection, the first symptoms appeared on the fourth day after infection. Before this, on the third day, the researchers observed the activation of defense mechanisms—MAIT cell activation, depletion of inflammatory monocytes, and global activation of interferon signaling in the blood.
Mild fever, nasal congestion, and sore throat emerged on the fourth day, while by the fifth day, peak immune responses and infected cells were detected. By the eighth day, most participants had lost their sense of smell, and by the tenth day, symptoms began to subside, coinciding with the activation of adaptive immunity.
How the Immune System Responds to COVID-19
- Persistent Infections: In cases leading to COVID-19, immune cells began activating only on the fifth-day post-infection, with their numbers continuing to increase until the tenth day.
- Transient Infections: When the virus failed to establish itself, immune cells were activated on the first-day post-infection, after which their numbers decreased, which indicates that a rapid immune response can prevent the development of a full-blown infection.
- Abortive Infections: Where the virus failed to take hold, there was an increase in CD4 and CD8 T-cells on the first day.
In both persistent and transient infections, innate immune cells—dendritic cells, natural killer cells, and mucosa-associated invariant T-cells (MAIT)—were initially activated, followed by the engagement of adaptive immune cells, underscoring the importance of a swift innate immune response in fighting the virus and preventing its spread.
Interferon System Activation: First in Blood, Then in the Nose
The interferon (IFN) system is activated when the coronavirus enters the body. IFN signals mobilize all immune cells in the blood. Interestingly, IFN system activation begins in the blood earlier than at the site of viral entry—the nasal epithelium, possibly due to the rapid spread of IFN signals through the lymphatic system. In participants with persistent infection, interferon was activated in blood cells and the nasopharynx on the third and fifth days after infection, which was particularly evident in γδ T-cells of the nasopharynx, which were fully activated by interferon by the fifth-day post-infection. Such activation was not observed in participants with abortive or transient infections. The IFN response in the blood starts as early as the second-day post-infection, helping to contain the virus before it can spread widely.
Rapid Decline in Inflammatory Monocytes
The scientists found that immune cells respond to the coronavirus even before clinical symptoms appear. For example, MAIT cells are activated, and the number of inflammatory monocytes decreases. In participants with persistent infection, the level of myeloid cells (dendritic cells, macrophages, and monocytes) in the nasopharynx decreased on the third-day post-infection. These early reactions may serve as biomarkers for detecting viral contact and could help prevent severe COVID-19.
The reduction in myeloid cells was due to their redistribution—these cells migrated from the blood to tissues where the virus was being fought. A decrease in inflammatory monocytes in the blood was observed in all participant groups. Inflammatory monocytes, which play a role in the immune response, showed high levels of molecules such as IL1B, IL6, and CXCL3, indicating an immediate reaction from the body to the virus, even if a persistent infection does not develop.
Activation of MAIT Cells
MAIT cells, or mucosa-associated invariant T cells, are a specialized type of immune cell found in mucosal tissues, playing a crucial role in protecting the body against infections. MAIT cells can be classified into two subgroups: classical and activated. Activated MAIT cells exhibit heightened cytotoxicity, meaning they can effectively target and destroy infected cells.
By the third day post-infection, nearly all MAIT cells in the blood of participants with persistent infections became activated. This activation of MAIT cells was also observed in cases of abortive and transient infections, indicating that MAIT cells are capable of rapidly responding to the presence of the virus. These findings suggest that MAIT cells and inflammatory monocytes play an essential role in the quick immune response to SARS-CoV-2, even when viral exposure does not lead to a sustained infection or subsequent COVID-19.
Viral RNA Peaks on the 7th Day
Infected cells were found almost exclusively in the nasopharynx of participants with persistent infections. The viral load peaked on the seventh day post-infection and sharply declined by days 10-14.
Viral RNA was detected in both immune and epithelial cells of the nasopharynx. Surprisingly, SARS-CoV-2 RNA was found in CD8 T cells despite the absence of ACE2 and TMPRSS2 receptors on their surface—receptors typically used by the coronavirus to enter cells. However, unlike goblet and ciliated cells in the nasopharynx, CD8 T cells cannot support coronavirus replication. The presence of viral RNA in CD8 T cells suggests that these T cells either become non-productively infected or capture viral fragments from surrounding cells.
Interestingly, the activation of interferon signaling at the site of viral entry on days 5-7 post-infection coincides with the peak of infected cells and a robust immune cell attack on the virus.
Hyperinflation of Ciliated Cells as the Cause of Viral Spread
Ciliated cells play a critical role in the spread of SARS-CoV-2. A small cluster of these cells exhibited an extremely high viral load—more than 1000 viral RNAs per cell. In contrast, other infected cells typically contained fewer than 10 viral RNAs.
Despite making up only 4% of all infected cells, hyperinfected cells harbored 67% of the total viral RNA, effectively becoming the primary factory for viral particles. Additionally, hyperinfected cells activate anti-inflammatory molecules, suppressing the interferon response and aiding the virus’s spread throughout the body.
HLA-DQA2 Gene Associated with Milder COVID-19 Course
Participants who did not develop symptoms had higher pre-infection levels of the HLA-DQA2 gene expressed in their blood immune cells and nasopharynx. This gene is associated with a milder course of COVID-19. The HLA-DQA2 gene helps the immune system effectively combat the virus, reducing the risk of it spreading throughout the body.
Activation of the Adaptive Immune System
By the tenth day post-infection, the adaptive immune system began to take action. Alongside B cells, which produce antibodies, T cells also became activated. Activated regulatory T cells peaked two weeks after infection, while other immune cells returned to normal levels. These activated regulatory T cells played a crucial role in reducing inflammation after the virus had been cleared, coinciding with the disappearance of nearly all infected cells.
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Reference
Human SARS-CoV-2 challenge uncovers local and systemic response dynamics
