New crown immunity "son preference"? Nature: The new crown virus changes the immune system, and men are more likely to trigger excessive immune responses!

The human immune system is a defense network covering the whole body, which has the role of immune surveillance, defense, and regulation, and in the war against the new coronavirus, the immune system has made great contributions, and we feel more than ever how important
it is to have a sound immune system.
Although it is now understood that the new crown virus infection will have a lasting functional effect on the immune system after recovery, it is still unclear how they affect the body's immune homeostasis, and will the human immune system return to its previous state after infection with the new crown? It's also unclear whether the coronavirus will change the body's immune system response to other threats?

On January 4, 2023, researchers from the National Institute of Allergy and Infectious Diseases and Yale University published a research paper
titled "Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19" in the top international journal Nature 。 Studies have found that the long-term effects of new coronavirus infection on the immune system are related to the sex of the individual, and that viral infection affects the basic immune status of humans, which in turn affects future immune responses
.
The research team first recruited symptomatic and asymptomatic people who recovered from the new coronavirus infection, as well as healthy controls (Figure 1a).

After drawing the blood of the volunteers, the whole blood transcriptome was used for multi-omics analysis, and 138 surface proteins and transcriptomes were analyzed by CITE-seq (single-cell transcriptome and surface protein sequencing technology), and serum proteins, antibody characterization, and various hematological parameters
were also studied.
Here, the authors first assess the baseline differences between those who recovered from Covid and those who were healthy, as well as the differences
before vaccination.
It was found that an increase
in male-specific monocyte frequency could still be detected months after recovery from mild infection.
Figure 1: Study overview and baseline differences[1] Next, the research team explored whether COVID-19 infection affects an individual's immune response
to non-coronavirus infection.
Study participants were vaccinated with seasonal influenza quadrivalent vaccine and followed up for up to 100 days, at days 1, 7, and 28, to assess vaccine response at the serology, molecular, and cellular levels (Figure 2), Figure 2: Differences in sex-specific responses to influenza vaccination in individuals who have recovered from COVID-19 and matched controls[1] The authors chose this vaccine in part because of its importance
to public health.
At the start of the study, the 2020-2021 flu season in the United States was approaching, and it was not clear whether the new coronavirus infection would affect the flu vaccine response
.
Therefore, the authors believe that influenza vaccination provides an excellent perturbation
for detecting the effects of mild coronavirus infection on the immune system.
By analyzing blood test data from days 1, 7, and 28, the authors found that COVR-M (men after recovery from mild infection) generally showed a stronger response than healthy COVR-F (women after recovery from mild infection) (Figure 2).

Based on previous studies of influenza vaccination in healthy adults, the authors hypothesize that a stronger early inflammatory response in men after recovery from mild infections will lead to a stronger humoral response, as it is known that an enhanced innate immune response caused by adjuvants enhances the adaptive response
.
In fact, at D7, men who have recovered from mild infections have a stronger increase
in influenza-specific plasmablasts than HC-M (healthy uninfected men).
This shows that compared with healthy men and women, male new crown survivors have a stronger response to the flu vaccine after receiving the flu vaccine
.
Essentially, the function of the immune system of men infected with the new crown has changed significantly, and this is also
the case long after recovery.
Further, the authors sought to link the basal level of the immune system to innate immunity and explore which variables may contribute to an enhanced interferon-related response in COVR-M, which may contribute to a more robust humoral response in COVR-M (Figure 3a).

Figure 3: Reasons for the increased IFNγ response on day 1 in men who have recovered from covid-19[1]

Mild COVID infection has been reported to induce a "bystander activation effect" of CD8+ T cells, a mechanism known as bystander activation by which the immune system can activate autoreactive T and B lymphocytes during pathogen infection in a way that is not related to antigens by creating an inflammatory environment
.
Interestingly, GPR56+ cells were also enriched with transcriptional markers associated with side-view T cell activation (Figure 3f).

Data analysis suggests that the increased interferon γ response in COVR-M after vaccination may have stimulated some cells that had a stronger response to inflammation, and they produced a stronger interferon response
to stimulation of inflammatory cytokines.
In general, men who have recovered from the new crown will produce more influenza antibodies and produce higher levels of interferon
after vaccination.
Taken together, the findings suggest that any infection or immune challenge has the potential to alter immune status, establishing new baseline setpoints that are encoded not only by the state of single-cell lineages but also by a network of interacting cell types
.
Furthermore, while baseline immune status for predicting future responses often varies between individuals, this study suggests that this baseline immune status may have been established by past infections and remained stable
until the next disturbance.
Thus, an individual's baseline immune status is determined by multiple previous
exposures.
In this study, the authors study the immune system's response to the novel coronavirus from a systemic immunological perspective, use the vaccination system to disrupt the immune system, and then use a variety of techniques to comprehensively assess its pre- and post-intervention state, analyze and model the resulting data set in a comprehensive way to reveal immune reactivity, infer interactions between immune system components, and ultimately understand how the immune response works
.
The study also validates earlier findings that men are more likely than women to die from an uncontrolled immune response
after contracting the new coronavirus.

It has been more than three years since the outbreak of new coronavirus pneumonia (COVID-19), in order to solve the epidemic and eliminate its adverse impact on human society, in the past three years we have carried out systematic research on the new coronavirus and achieved a large number of research results, which provides a solid theoretical support for us to develop new drugs and formulate epidemic prevention policies, but it is still not enough to be satisfied with the existing results, we still need more research to completely defeat the epidemic and restore our normal life order!

References:

1.
 Sparks, R.
, Lau, W.
W.
, Liu, C.
 et al.
 Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19.
 Nature (2023).
https://doi.
org/10.
1038/s41586-022-05670-5