Beyond schistosomiasis: unraveling co-infections and altered immunity

Abstract

Schistosomiasis is a neglected tropical disease caused by the helminth Schistosoma spp. and has the second highest global impact of all parasites. Schistosoma are transmitted through contact with contaminated fresh water predominantly in Africa, Asia, the Middle East, and South America. Due to the widespread prevalence of Schistosoma, co-infection with other infectious agents is common but often poorly described. Herein, we review recent literature describing the impact of Schistosoma co-infection between species and Schistosoma co-infection with blood-borne protozoa, soil-transmitted helminths, various intestinal protozoa, Mycobacterium, Salmonella, various urinary tract infection-causing agents, and viral pathogens. In each case, disease severity and, of particular interest, the immune landscape, are altered as a consequence of co-infection. Understanding the impact of schistosomiasis co-infections will be important when considering treatment strategies and vaccine development moving forward.

Keywords: HIV; Leishmania; Mycobacterium; Plasmodium; SARS-CoV-2; Salmonella; Schistosoma; Toxoplasma; Trypanosoma; UTI-causing agents; arboviruses; co-infection; cytomegalovirus; hepatitis; immunology; intestinal protozoa; soil-transmitted helminths.

Fig 1

Schistosoma pathobiology. Intestinal schistosomiasis is represented by Schistosoma mansoni (Sm) transmitted by Biomphalaria spp. snails, and urinary schistosomiasis is represented by S. haematobium (Sh) transmitted by Bulinus spp. snails. Upon cercarial entry into the skin, schistosomes induce T_REG responses. From circulation to adult worm oviposition, immune responses are predominately T_H1. As adult worms pair and lay eggs in the intestinal mesentery (Sm) and bladder venus plexus (Sh), soluble egg antigens drive T_H2 immunity. Eggs are excreted in feces (Sm) and urine (Sh) to continue the life cycle. Chronic schistosomiasis upregulates T_REG responses to protect the host from severe pathology and promote parasite persistence. Illustrative images are not to scale.

Fig 2

Schistosoma mansoni (Sm) and S. haematobium (Sh) co-infection. In co-infections with Sm and Sh, ectopic egg elimination occurs, with both Sm and Sh eggs found in urine and, to a lesser extent, in feces. Male worms determine the residency of paired couples. Sm male and Sh female couplings (M) are more common, these pairs reside in the venous plexus similar to Sh couples; Sm couples reside within the intestinal mesentery. Co-infection reduces the risk of liver pathology but increases parasite burdens, urogenital pathology, and T_H2 immune responses. Illustrative images are not to scale.

Fig 3

Proposed immunological effects of schistosomiasis and malaria co-infection. In recent epidemiological studies and in mouse co-infection models, schistosomiasis leads to an increase in T_REG cells, an increase in anti-malaria antibodies and in IL-4 (T_H2-skewed response) which appear to reduce the levels of Plasmodium and decrease pathology. However, co-infection increases the risk of anemia. More research must be done to clarify the effects of other aspects of the immune response since they remain unclear.

Fig 4

Proposed immunological effects of schistosomiasis and tuberculosis co-infection. In co-infections of schistosomiasis and tuberculosis, the helminth promotes type 2 responses and type 2 granuloma formation, IL-4 expression, and T_REG responses which may lead to worsened TB outcomes. Research suggests that schistosomiasis reduces CD4+ T cell IFNγ responses crucial for tuberculosis immunity, while tuberculosis reduces helminth-specific γδ T cell responses.

Fig 5

Proposed immunological effects of schistosomiasis and human immunodeficiency virus co-infection. Schistosomiasis exacerbates T_H2 responses, hindering T_H1 responses, including CD8+ T cells vital for viral control. Additionally, schistosomiasis [especially female genital schistosomiasis (FGS)] induces immune and pathology changes that may increase HIV susceptibility and transmission risk. Finally, schistosomiasis causes CD4+ T cell and mast cell expansion prior to HIV infection, leading to a larger HIV reservoir in the host. Post-infection, HIV contributes to a decline in CD4+ T cell counts. Co-infections of schistosomiasis and HIV may lead to increased hepatosplenic disease.

Fig 6

Schistosoma and co-infections world map. The navy-blue shading on the map indicates regions where Schistosoma spp. are endemic. Within these areas, colored dots mark co-endemic regions for other pathogens. Geographical regions are categorized as South America, Africa, the Middle East, India, China, and the Southeast Asian nations. Intestinal protozoa were omitted as they are ubiquitous. Salmonella, SARS-CoV-2, and cytomegalovirus are also ubiquitous and have been marked in areas where they are most prevalent.