Review Systems analysis of innate and adaptive immunity in Long COVID, 2024, Peluso et al.

Systems analysis of innate and adaptive immunity in Long COVID
Peluso; Abdel-Mohsen; Henrich; Roan

Since the onset of the COVID-19 pandemic, significant progress has been made in developing effective preventive and therapeutic strategies against severe acute SARS-CoV-2 infection. However, the management of Long COVID (LC), an infection-associated chronic condition that has been estimated to affect 5–20% of individuals following SARS-CoV-2 infection, remains challenging due to our limited understanding of its mechanisms.

Although LC is a heterogeneous disease that is likely to have several subtypes, immune system disturbances appear common across many cases. The extent to which these immune perturbations contribute to LC symptoms, however, is not entirely clear. Recent advancements in multi-omics technologies, capable of detailed, cell-level analysis, have provided valuable insights into the immune perturbations associated with LC. Although these studies are largely descriptive in nature, they are the crucial first step towards a deeper understanding of the condition and the immune system’s role in its development, progression, and resolution.

In this review, we summarize the current understanding of immune perturbations in LC, covering both innate and adaptive immune responses, and the cytokines and analytes involved. We explore whether these findings support or challenge the primary hypotheses about LC’s underlying mechanisms. We also discuss the crosstalk between various immune system components and how it can be disrupted in LC. Finally, we emphasize the need for more tissue- and subtype-focused analyses of LC, and for enhanced collaborative efforts to analyze common specimens from large cohorts, including those undergoing therapeutic interventions. These collective efforts are vital to unravel the fundaments of this new disease, and could also shed light on the prevention and treatment of the larger family of chronic illnesses linked to other microbial infections.

Link | Paywall (Seminars in Immunology)

 

Box 1 Outstanding Immunology Questions.

• Is there a role for NK cell function or dysfunction in LC?

• Do individuals with LC harbor unique antibody profiles with regards to specificity, isotype subclass, and Fc-mediated effector functions?

• Are viral-specific T cells functionally impaired during LC?

• Are there unique phenotypic and functional features of immune cells residing within tissues of individuals with LC?

• How can persisting SARS-CoV-2 evade detection and elimination by the innate and adaptive immune system?

• Are different subtypes of LC driven by distinct immunological perturbations?

• What are the impacts of vaccination, re-infection, and SARS-CoV-2 variant in the immunology of LC?

• What immune features of LC are sex-specific, and driven by sex hormones?

• What are the effects of menopause and female-specific inflammatory diseases (endometriosis, PCOS) on LC development and progression in women?

• Which immune perturbations in children with LC are shared with those observed in adults?

• Are there shared immunological perturbations between LC and other infection-associated chronic conditions?

• Would targeting any of these immune pathways with anti-inflammatory, immunomodulatory, or immunosuppressive therapeutic approaches provide benefit to people experiencing LC?