Immunological Foundations of Long COVID UCM-Madrid
Scientic Supervisor / Contact Person
Name and Surname
Narcisa Martínez-Quiles
ORCID (link)
Researcher ID (link)
Localization & Research Area
Faculty / Institute
Faculty of Medicine
Department
Immunology (Ophthalmology and ENT)
Research Area
Life Sciences (LIF)
MSCA & ERC experience
Research group / research team hosted any MSCA fellow?
No
Research group / research team have any ERC beneficiaries?
No
Research Team & Research Topic
Research Team / Research Group Name (if any)
Long covid immunology group
Website of the Research team / Research Group / Department
Brief description of the Research Team / Research Group / Department
The PI studied the signal transduction pathways of the immunodeficiency called Wiskott-Aldrich syndrome. Previous studies focused on cortactin regulation using the infection enteropathogenic Escherichia coli (EPEC) model, which adheres to cells by forming actin pedestals. During this period, we established collaborations to study the role of cortactin in the infection of cells by Helicobacter pylori and by Coxiella. Another line of research developed has been the study of the regulation of cortactin by post-translational modifications and its role in cell spreading. Thus, we have characterized a novel cortactin-FAK complex that functions as a molecular clutch in integrin activation. In addition, we found a competition between the acetylation and tyrosine phosphorylation of cortactin and that phosphorylation inhibits cell spreading. We have some pending publications regarding the immune cortactin paralogue HS1 protein that we will try to finish as well (molecular biology studies).
However, during the pandemic, the PI focused on studying the immune response of a group of patients that at that point had sequelae from a previous COVID infection. Nowadays we know they were suffering post-acute sequelae of COVID-19 (PASC) or Long COVID.
It is estimated that more than 700 million coronavirus disease 2019 (COVID-19) cases were reported worldwide during the pandemic period and that at least 7 % of infections in adults and 1 % in children could have led to the development of diverse health sequelae commonly known as Long COVID (LC), a term coined by the patients themselves (1, 2).
LC syndrome, also named post-acute sequelae of COVID-19 (PASC), comprises an extensive variety of symptoms that continue or develop two to three months after the acute phase of the infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (3).
LC develops in people of all ages but presents a higher incidence in women. It affects several organs/ systems and presents a mild, moderate, or severe disease progression. Manifestations of the syndrome involve neurological, cardio-respiratory, and musculoskeletal systems. Frequently reported symptoms are fatigue, brain fog, muscle and chest pain, dyspnea, and heart arrhythmias. Importantly, altered immune response manifestation can include autoimmunity, hyperinflammation and reactivation of endogenous viruses (4).
Notably, considering that SARS-CoV-2 is still circulating, we must consider that the risk of developing LC could increase with repeated infections (5). Therefore, LC is becoming an increasingly relevant public health problem due to its high incidence and often disabling symptomatology (6).
Additionally, there has been a significant increase in the number of sickness leave that in our opinion and in that of experts from primary care (6) can be partially related to the pandemic and probably to undiagnosed Long COVID symptoms such as fatigue, depression, post-exertional malaise, respiratory problems etc. Therefore, we think Long COVID represents a word health challenge and therefore, it is critical to investigate the immune response in Long COVID patients.
References
1. Z. Al-Aly et al., Long COVID science, research and policy. Nat Med 30, 2148-2164 (2024).
2. E. Harris, US Survey: About 7% of Adults, 1% of Children Have Had Long COVID. JAMA
330, 1516 (2023).
3. E. W. Ely, L. M. Brown, H. V. Fineberg, E. National Academies of Sciences, C. Medicine
Committee on Examining the Working Definition for Long, Long Covid Defined. N Engl J
Med 391, 1746-1753 (2024).
4. H. E. Davis, L. McCorkell, J. M. Vogel, E. J. Topol, Long COVID: major findings,
mechanisms and recommendations. Nat Rev Microbiol 21, 133-146 (2023).
5. M. L. Bosworth et al., Risk of New-Onset Long COVID Following Reinfection With Severe
Acute Respiratory Syndrome Coronavirus 2: A Community-Based Cohort Study. Open
Forum Infect Dis 10, ofad493 (2023).
6. D. Suarez, E. Pascual, J. R. Soravilla, [Long covid and disability]. Semergen 50, 102189
(2024).
However, during the pandemic, the PI focused on studying the immune response of a group of patients that at that point had sequelae from a previous COVID infection. Nowadays we know they were suffering post-acute sequelae of COVID-19 (PASC) or Long COVID.
It is estimated that more than 700 million coronavirus disease 2019 (COVID-19) cases were reported worldwide during the pandemic period and that at least 7 % of infections in adults and 1 % in children could have led to the development of diverse health sequelae commonly known as Long COVID (LC), a term coined by the patients themselves (1, 2).
LC syndrome, also named post-acute sequelae of COVID-19 (PASC), comprises an extensive variety of symptoms that continue or develop two to three months after the acute phase of the infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (3).
LC develops in people of all ages but presents a higher incidence in women. It affects several organs/ systems and presents a mild, moderate, or severe disease progression. Manifestations of the syndrome involve neurological, cardio-respiratory, and musculoskeletal systems. Frequently reported symptoms are fatigue, brain fog, muscle and chest pain, dyspnea, and heart arrhythmias. Importantly, altered immune response manifestation can include autoimmunity, hyperinflammation and reactivation of endogenous viruses (4).
Notably, considering that SARS-CoV-2 is still circulating, we must consider that the risk of developing LC could increase with repeated infections (5). Therefore, LC is becoming an increasingly relevant public health problem due to its high incidence and often disabling symptomatology (6).
Additionally, there has been a significant increase in the number of sickness leave that in our opinion and in that of experts from primary care (6) can be partially related to the pandemic and probably to undiagnosed Long COVID symptoms such as fatigue, depression, post-exertional malaise, respiratory problems etc. Therefore, we think Long COVID represents a word health challenge and therefore, it is critical to investigate the immune response in Long COVID patients.
References
1. Z. Al-Aly et al., Long COVID science, research and policy. Nat Med 30, 2148-2164 (2024).
2. E. Harris, US Survey: About 7% of Adults, 1% of Children Have Had Long COVID. JAMA
330, 1516 (2023).
3. E. W. Ely, L. M. Brown, H. V. Fineberg, E. National Academies of Sciences, C. Medicine
Committee on Examining the Working Definition for Long, Long Covid Defined. N Engl J
Med 391, 1746-1753 (2024).
4. H. E. Davis, L. McCorkell, J. M. Vogel, E. J. Topol, Long COVID: major findings,
mechanisms and recommendations. Nat Rev Microbiol 21, 133-146 (2023).
5. M. L. Bosworth et al., Risk of New-Onset Long COVID Following Reinfection With Severe
Acute Respiratory Syndrome Coronavirus 2: A Community-Based Cohort Study. Open
Forum Infect Dis 10, ofad493 (2023).
6. D. Suarez, E. Pascual, J. R. Soravilla, [Long covid and disability]. Semergen 50, 102189
(2024).
Research lines / projects proposed
Currently, there is an extensive body of literature examining antibody production against SARS-CoV-2 essential proteins, such as the Nucleocapsid and the Spike, their correlation with symptoms and severity during the acute phase of the infection, and in response to vaccination (7, 8). Regarding the Spike, it is a trimeric protein composed of two main domains, the S1 is responsible for the entrance while the S2 for the virus‐cell membrane fusion. The S1 includes the receptor binding domain (RBD) (9). Accordingly, numerous studies have determined total immunoglobulin G (IgG) and IgG1 subclass against the S1 and the RBD (10), while there are only a few studies using the full-length (FL) protein.
However, only a few studies have investigated the production of Immunoglobulins (Igs) in LC cohorts. One of such study reported higher titers of IgG anti-S1 in LC individuals compared to fully recovered individuals, though the amounts of Spike and RBD specific IgGs were similar in both groups (11). On the contrary, a second study investigated both S1 and RBD Spike IgG antibodies and found decreased antibody titers in LC individuals (12). Therefore, more research is needed to clarify this crucial subject to comprehend the role of the immunological response in the development of LC (13).
In conclusion we think it is relevant to study the subclass response of LC patients to vaccination and to infection. On the other side, the reasons behind LC have been investigated pointing to diverse underlying causes (4), such as infection-related immune dysregulation and autoimmunity, excessive inflammation, incomplete virus clearance, and reactivation of latent viruses, all of which could be interrelated.
In this proposal, we will contribute to the problems mentioned by studying mainly the antibody response in an LC cohort, with respect to a COVID-recovered control cohort.
Additionally, and based on our own results, we will analyze relevant immune factors that could condition the orientation of the immune response that would condition the antibody response itself.
However, only a few studies have investigated the production of Immunoglobulins (Igs) in LC cohorts. One of such study reported higher titers of IgG anti-S1 in LC individuals compared to fully recovered individuals, though the amounts of Spike and RBD specific IgGs were similar in both groups (11). On the contrary, a second study investigated both S1 and RBD Spike IgG antibodies and found decreased antibody titers in LC individuals (12). Therefore, more research is needed to clarify this crucial subject to comprehend the role of the immunological response in the development of LC (13).
In conclusion we think it is relevant to study the subclass response of LC patients to vaccination and to infection. On the other side, the reasons behind LC have been investigated pointing to diverse underlying causes (4), such as infection-related immune dysregulation and autoimmunity, excessive inflammation, incomplete virus clearance, and reactivation of latent viruses, all of which could be interrelated.
In this proposal, we will contribute to the problems mentioned by studying mainly the antibody response in an LC cohort, with respect to a COVID-recovered control cohort.
Additionally, and based on our own results, we will analyze relevant immune factors that could condition the orientation of the immune response that would condition the antibody response itself.
Key words
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