What Microbes Can Lead to Post Infection Chronic Illnesses?
Epstein-Barr Virus
The Epstein-Barr Virus (EBV), one of 9 known human herpesvirus types, and the most common viruses to infect humans, has long been associated with an array of different diseases and conditions, including systemic lupus erythematosus, Sjögren syndrome and MS. This double stranded DNA virus is primarily transmitted through saliva, earning it the moniker "the kissing virus" and is the known etiological agent of infectious mononucleosis.
The principal targets of EBV infection are B cells, the type of white blood cells that make antibodies. EBV can directly infect B cells in the oral cavity or access them indirectly via oral epithelial cells. Following infection, EBV can establish lifelong latency in infected B cells. Reactivation of EBV can be triggered by stress or immunosuppressant treatment. Upon reactivation, the virus can be transmitted to new hosts.
Researchers have been focusing on pathogenic mechanisms that lead to post infection chronic stimulation of the immune system. One hypothesis is that pathogen remnants (i.e., viral RNA), which contain pathogen associated molecular patterns (PAMPs) stay in the host at undetectable levels and persistently activate host pathogen recognition receptors. Constant activation of these receptors can cause continuous inflammation, subsequently damaging host tissue and potentially initiating autoimmune activation. This is not exclusive to EBV and applies to a wide range of post-acute infection syndromes.
The establishment of latency to later propagate throughout a host's lifespan may help explain the connection between EBV and autoimmune activation. One example is the link between Pityriasis lichenoides chronica (PLC) and EBV. PLC is a rare skin disease that results in scaly, red or brown bumps across the trunk and extremities, which can come and go (relapsing and remitting) for months to years. Research indicates that PLC papules are remnants of different subsets of overactivated T cells that remain after viral infections. While the cause of PLC ultimately remains unknown, it has been linked to EBV as a hypersensitivity reaction in patients with elevated EBV titers. It is still unknown whether recent infection alone is the cause of PLC, or if there is more to this immune dysregulation that gets repeatedly activated from previous EBV infection. Similarly to EBV, post-infected COVID-19 patients have been diagnosed with the inflammatory rash Pityriasis Lichenoides et Varioliformis Acuta.
Another hypothesis on the cause of post-acute infection syndromes is that acute infections may induce autoimmune activation by impairing regulatory T cells or through molecular mimicry of self-antigens by the pathogen. Studies have shown that EBV is linked to a >30-fold increased risk of developing MS, and an EBV protein (EBV nuclear antigen 1) has been found to elicit auto-antibody cross reactivity with central nervous glial cell adhesion molecules of the host.
Borrelia burgdorferi
Borrelia burgdorferi is another example of a pathogen that appears to cause post-acute infection syndromes. B. burgdorferi is the bacterium that causes Lyme disease and is transmitted to humans by blacklegged ticks in different regions of the U.S. and abroad. While Lyme disease can be treated with antibiotics, post-treatment Lyme disease syndrome (PTLDS) is a rising health concern. PTLDS is a condition where patients experience chronic fatigue, pain and cognitive dysfunction for at least 6 months following antibiotic treatment and clearance of infection.
There is debate in the Lyme disease research field about the plausibility of PTLDS as a syndrome caused by Lyme disease itself, as many symptoms associated with PTLDS are seen in other post-acute infection syndromes. The U.S. Center for Disease Control (CDC) does recognize long term symptoms associated with post Lyme disease clearance as PTLDS. Potential causes of PTLDS may be permanent tissue damage following infection, an activated autoimmune response or an undetectable ongoing Borrelia infection. However, ongoing infections in the context of PTLDS have not been seen in clinical settings, and the CDC recommends that the term "Chronic Lyme disease" not be utilized as it implies that there is an ongoing bacterial infection causing PTLDS symptoms when the cause currently remains unknown.
One hypothesis on cause of PTLDS is loss of "tolerance building." In "tolerance building" carrier hosts show no symptoms of Lyme disease (i.e. arthritis, carditis) because an immune tolerance has been built to essentially ignore the bacteria, similar to how we mitigate inflammation in the gut microbiome with commensal bacteria. Linden Hu, M.D., a professor of immunology at Tufts Medical school, describes in ASM's Meet the Microbiologist podcast how this loss of tolerance building in humans may contribute to increased inflammation detrimental to the host. "If you knock out genes in animals that are involved in the innate immune pathway, you would have predicted that you'd get less inflammation, but what we actually see in many cases where you knock out components of the innate immune system is that you get increased inflammation," Hu explained. Researchers have found that B. burgdorferi infected patients with single nucleotide polymorphisms (SNPs) in the pathogen recognition receptor Toll like receptor 1 have higher inflammatory responses and subsequent antibiotic-refractory Lyme arthritis. Recently, Hu's group identified how a complex transcriptional network gets reprogrammed in macrophages during Borrelia infection to modulate long term inflammation in Lyme arthritis. Excitingly, in 2023 the National Institute of Allergy and Infectious Diseases (NIAID) announced it awarded 5 project awards to fund PTLDS research
