This theoretical paper, by the US author, discusses and speculates on the possible interactions between intracellular pathogens, such as viruses, bacteria, fungi and protozoan parasites when they concurrently infect the same host cells. The author also discusses how concurrent intracellular pathogens can lead to T-cell exhaustion and subvert immune defense, with severe consequences.
The chronic or latent infection of prolong duration with the first pathogen can create a cytokine environment where T-cells express multiple inhibitory receptors. At the same time, the infected cells express multiple inhibitory ligands for those inhibitory receptors. The author gives an example of chronic infection with the parasitic protozoan Toxoplasma gondii. This infection increases the number of inhibitory programmed death 1 (PD-1) receptors on T-cells, as well as the number of PD-ligands on cells infected with Toxoplasma gondii. The increased number of inhibitory receptors and their ligands facilitates their binding and subsequent activation of the inhibitory PD-1 receptors on T-cells.
The infection with the second pathogen
When T-cells express multiple inhibitory receptors, and cells infected with the first pathogen express multiple inhibitory ligands for those inhibitory receptors, a novel infection with the second pathogen, especially with a virulent pathogen that creates large antigen titer, can lead to an accelerated exhaustion of T-cells to escape T-cell control. For example, the first pathogen is a protozoan parasite or bacteria that infects host cells, and the second pathogen is a virulent virus that can infect the same host cells already infected by the first pathogen. The pre-existing inflammation and cytokine environment created by the first pathogen could enable the second pathogen to achieve an accelerated T-cell exhaustion and to overwhelm a host’s remaining adaptive immune system defenses.
Concurrent intracellular infection enables the second pathogen, possibly one that produces large antigen titer, to reuse inhibitory ligands for inhibitory receptors (such as PD-L1), that have already been expressed by the same infected cells. Since the infected host cells already extensively express inhibitory ligands, the reuse of the inhibitory ligands by the second pathogen is facilitated. Reusing of inhibitory ligands for inhibitory receptors accelerates the T-cell exhaustion towards the second pathogen, thereby enabling the second pathogen to overcome the host’s adaptive immune responses. During viral epidemics, when the second pathogen infection produces high antigen titer, the accelerated exhaustion of T-cells may result in a high mortality rate.
If the host is able to survive the accelerated T-cell exhaustion for the second pathogen and a faster-paced second pathogen infection from the weakened T-cell functionality, then the first pathogen is a threat. The activation of inhibitory receptors on T-cell subsets could result in the exhaustion of CD8+ T-cells for both the first and second pathogens. If the first pathogen is a latent infection, T-cell exhaustion for the first pathogen can enable a reactivation of the latent first pathogen, with severe consequences. The reactivation of a latent first pathogen, for example, Toxoplasma gondii, can lead to severe consequences, like encephalitis, hepatitis, or myocarditis. In addition, the interaction between intracellular pathogens is illustrated by the interaction between human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. It has been estimated that one third of global HIV mortality is caused by the reactivation of Mycobacterium tuberculosis by HIV.
The author also emphasizes the particularly dangerous outcome of infection caused by an immunologically novel second pathogen. In the first-time infections with the second pathogen, the accelerated T-cell exhaustion could be particularly dangerous if the follicular helper CD4+ T-cells from germinal centers are suppressed. The number and/or affinity selection/maturation of antibodies (produced from B-cells by CD4+ T-cell assistance) become inadequate to control the second pathogen. Follicular helper CD4+ T-cells are critical for the maturation of antibody affinity, isotype switching, generation of memory B-cells and differentiation of B-cells into immunoglobulin (antibody) secreting plasma cells.
T-cell exhaustion was observed in severe cases of COVID-19, and this could be the fundamental driver of COVID-19 mortality. T-cell exhaustion can affect CD8+ T-cells and CD4+ T-cells that would have controlled the virus, as well as follicular helper CD4+ T-cells, mainly in germinal centers in lymph nodes and the spleen. Studies have shown that patients with severe COVID-19 have a higher proportion of less-effective IgM immunoglobulins compared to those observed in patients with mild COVID-19 and controls.
Considering T-cell exhaustion in long COVID patients, the author stated that the inflammatory and cytokine environment that is generated during the T-cell exhaustion for the first pathogen, leads to a more rapid T-cell exhaustion for the second pathogen. The determination of a delay time for the second pathogen to achieve T-cell exhaustion can be based on the following: 1. the time required for the expression of inhibitory ligands on host cells infected by the second pathogen, if they are not already expressed, and 2. the shorter time (24 h–72 h) required for T-cells for the second pathogen to express several inhibitory receptors. This short time can be fatal, since accelerated T-cell exhaustion for the second pathogen may precede an effective antibody defense against the second pathogen by affinity selection and antibody isotype switching.
The author pointed out that prolonged period of lymphocyte exhaustion for T-cells and NK-cells was observed in COVID-19 survivors, several weeks after infection. Multiple lymphocyte exhaustion could be a major cause of the post-infection symptoms, collectively known as long COVID.
The author further discusses numerous pathways for T-cell exhaustion and/or T-cell suppression, which are shared by the first and second pathogens, including cytokines (IL-10, transforming growth factor-β (TGF-β), type I interferons α and β) and cells that impair T-cell functionality. Regulatory T-cells (TREG cells) also play a role in the exhaustion and/or suppression of T cells. TREG cells impair antigen-specific T-cells by secreting inhibitory cytokines like IL-10, interleukin-35, and TGF-β. TREG cells also use their IL-2 receptors (CD25) to lower background levels of IL-2 and decrease the replication of T-cells.
The author also examines the mechanisms by which intracellular pathogens subvert innate and adaptive immune defenses. Some viral pathogens, such as Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus and human cytomegalovirus, are known to utilize or synthesize multiple types of short non-coding ribonucleic acids (RNAs). These RNAs can regulate hundreds of host cell genes by interfering with gene expression and messenger RNA processing. This allows the virus to evade or disable several immune or intracellular defenses. The disruption of interferon-stimulated genes helps the Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus and human cytomegalovirus in evading recognition by innate immune cells (NK-cells) and adaptive immune cells (T-cells). Pro-pathogenic effects of non-coding RNAs can occur throughout all phases of a cellular infection. For instance, Epstein-Barr viral non-coding RNAs can be synthesized and released during the prelatent time after infection, during viral latent infection and during the lytic stage. This interferes with the cellular defenses against other intracellular pathogens that concurrently infect the same host cell. The reactivation of latent intracellular pathogens can be facilitated by the inhibition of cellular immune defenses against the second pathogen, either by pathogenic use of non-coding RNAs or/and proteins against interferon-stimulated genes.
This article was published in Heliyon.
Roe K. Concurrent infections of cells by two pathogens can enable a reactivation of the first pathogen and the second pathogen’s accelerated T-cell exhaustion. Heliyon 8 (2022) e11371 https://doi.org/10.1016/j.heliyon.2022.e11371