Helminths, parasitic worms, have co-evolved with us for millennia, and, given their ability to often live in relative equilibrium with their hosts, have even been called “old friends”. These old friends, however, are exquisitely capable of manipulating host biology to allow them to survive and reproduce in an otherwise hostile environment (recently reviewed by Boyett and Hsieh):
The host environment can be unfriendly to parasites through immune responses, as well as more physiologic activities such as mucus production (to entrap parasites and facilitate their subsequent expulsion) and diarrhea (to likewise facilitate parasite expulsion). Interestingly, parasite expulsion benefits both the parasite and host, since it allows the parasite to complete the portion of its life cycle that exists outside the host.
A fascinating aspect of host-parasite interactions is the concept of “collateral damage”, inadvertent host modulation by the parasite. For example, Schistosoma haematobium, one of our model organisms, causes bladder cancer through poorly understood mechanisms, but nonetheless it is highly unlikely that this parasite has evolved to kill off its host (and thus, itself) by causing lethal cancers. It is more probable that some of the pathways by which S. haematobium alters the bladder epithelium to enable egg expulsion into the urinary stream happen to sometimes lead to carcinogenesis. Conversely, the chronic host inflammatory responses to S. haematobium eggs lodged in the bladder wall may be equally or more important pro-oncogenic factors.
Another means by which S. haematobium modulates the human host is by skewing immune responses directed against the parasite. There has been a long-standing but ill-defined association between S. haematobium infection and increased susceptibility to bacterial uropathogen co-infection. Theories to explain this association have included detection bias, obstruction, and immunomodulation. Detection bias refers to the possibility that patients with S. haematobium infection happen to be incidentally diagnosed with bacterial co-infection due to more intensive testing of their urine. In this scenario, the association is not a true biological one. The obstruction theory of S. haematobium-bacterial uropathogen co-infection states that the urinary tract fibrosis caused by S. haematobium leads to obstruction and urinary stasis, factors known to promote bacterial urinary tract infection. Finally, immunomodulation refers to the accepted ability of schistosomes to polarize the immune responses of their human hosts. Specifically, schistosomes are established inducers of potent type 2 immunity, exemplified by cytokines such as interleukin-4 (IL-4). Type 2 immunity in this setting leads to granuloma formation, aggregates of immune cells around parasite eggs which both sequester the rest of the host from the highly pro-inflammatory eggs and parasite toxins, as well as mediate subsequent expulsion of eggs from the body.
We recently published a paper demonstrating that S. haematobium-induced IL-4 abrogates the activation of natural killer T cells that would otherwise effectively clear bacterial uropathogen co-infection (Hsieh, Fu, and Hsieh). In a sense, S. haematobium has evolved to become an “accidental saboteur”, since chronic infection confers increased susceptibility to bacterial uropathogen co-infection, and yet this susceptibility does not grant any apparent benefits to the parasite.
Interestingly, co-infection is thought to potentially increase risk of bladder cancer, possibly via production of carcinogenic compounds such as nitrosamines. Given all of these effects of S. haematobium infection on the human host, this parasite is not an “old friend”. At best it is an ancient “frenemy”. Keep you friends close, your enemies closer, and your frenemies closest. More research on helminths will help us eradicate these major sources of human suffering through diagnostic, drug, and vaccine development.
Boyett, D., & Hsieh, M. (2014). Wormholes in Host Defense: How Helminths Manipulate Host Tissues to Survive and Reproduce PLoS Pathogens, 10 (4) DOI: 10.1371/journal.ppat.1004014
Hsieh, Y., Fu, C., & Hsieh, M. (2014). Helminth-Induced Interleukin-4 Abrogates Invariant Natural Killer T Cell Activation-Associated Clearance of Bacterial Infection Infection and Immunity, 82 (5), 2087-2097 DOI: 10.1128/IAI.01578-13