Often when we talk about a particular disease, we get caught up in the idea of that disease in isolation. We think only of just that disease, and not the real world implications of that disease. Unfortunately, the reality is that many people in developing nations are afflicted with many debilitating diseases, not just the disease in question. For example, individuals in Africa have a host of debilitating diseases to contend with, including helminth caused diseases, HIV, malaria, hepatitis, and typhoid fever just to name a few. When an individual has concurrent disease (or more than one disease at a time), this can greatly influence the progression of all diseases in question.
In this past weeks’ discussion, we talked about how helminth infections can change or alter the disease progression of malaria. Given the pervasiveness of helminth infections in the developing world (the World Health Organization estimates that 2 billion people are infected with soil-transmitted helminths alone, worldwide), to gain an understanding of the actual disease progression of malaria, we must understand how helminths affect the immune system.
Previous research has shown Helminths play a very important role in modifying the immune system of the infected host. This is a defense mechanism to allow for the survival of the helminth while also prevent the hosts’ immune from going into ‘overdrive’. In a typical infection, the hosts’ immune system will mount a response to get rid of the invading virus, bacteria etc. This usually involves various amounts of localized inflammation, however, given the large size of helminthes, mounting a large immune response towards the helminth would result in a lot of damage to the host as well. As a result, host and helminth have co-evolved to produce an immune response that will keep the helminth in check, without harming the host too much. It is important to remember that helminths do not usually cause severe pathology, and therefore the host can ‘tolerate’ having a few helminths kicking around in its system. It is not worth the damage that would result from attacking the helminth head on.
Broadly speaking there are two major branches of the immune system, the innate and the adaptive immune system. The innate immune system can identify foreign pathogens, and usually eradicate the invader by releasing granules (small particles) that can break down the foreign particles. However, due to the size of these pathogens, a great deal of granules would need to be released in order to kill and break down the worm. While this is certainly possible to get rid of the worm, it would most likely kill the host in the process. Because the helminth must survive until it can reproduce (usually a couple weeks depending on the species) it is not in the helminths best interest to let the host die. Therefore it tries to evade and suppress this aspect of the immune system. Various helminths have a plethora of different tools in their arsenal, which inhibit the innate immune response. This leaves the adaptive immune system.
The adaptive immune system (also known as the acquired immune system) is responsible for a more direct attack of pathogens compared to the more generalized action of the innate immune system. There are two main types of immune cells in the adaptive immune system, B-cells which are responsible for the production of antibodies, and T-cells (Effector [CD8+] and helper [CD4+]) which are responsible for carrying out the adapted immune response. The antigens present on the outside of the worm can be recognized by the T-cells (CD4+) after being presented by dendritic cells, which influences the type of immune response that occurs from the adaptive immune system. The CD4+ T-cell will usually differentiate into either a Th1, Th2 or Treg cell. Each of these cells release molecules known as cytokines, which signal other cells to perform certain actions. The Th1 cell releases cytokines (IFNγ) which is usually associated with pathological inflammation. Th2 cells releases cytokines (IL-4, IL-13), which suppresses the inflammation of the Th1 response, but still has some inflammatory processes. In the case of helminths there will be enough localized inflammation and regulation to keep the helminths ‘in check’ and prevent them from causing too much damage damage. The Treg cells are responsible for winding down the immune response and stopping the Th1 and Th2 responses.
Image courtesy of: http://www.nature.com/nri/journal/v7/n12/pdf/nri2199.pdf
In a typical helminth infection, Th1 immune responses will be down-regulated because this amount of inflammation is not good for either the host or the helminth (as mentioned previously). Helminths will secrete molecules that will drive the immune response towards a Th2 and Treg response to ‘tone down’ the immune system to reduce the amount of inflammation caused by the immune system. The exact mechanism of this has not yet been determined, but it is the focus of much research to identify these molecules and the hope is that they will be discovered soon.
Image courtesy of: http://www.nature.com/nri/journal/v3/n9/full/nri1183.html
This is generally broad overview of the affect helminths have on the immune system, for a more comprehensive summary of these effects please see the two Nature reviews on this topic (Protective immune mechanisms in helminth infection, Diversity and dialogue in immunity to helminths)
So how does all this nonsense relate to malaria infections?
Researchers have shown the helminths heavily influence the immune system in this manner (skewing it towards a Th2/Treg response compared to a Th1 response), to the extent that it compromises the hosts immune response to other pathogens such as malaria. If we look at the lifecycle of malaria:
Image courtesy of: http://www.cdc.gov/malaria/about/biology/
We can see that malaria goes through two stages in the host, one in the liver and one in the blood. Given the typical response to malaria (shown below), we can observe that the blood stages of the parasites will typically drive a Th1 mediated immune response in the host. Symptoms of acute malaria often include headache, fever, muscle pains, chills, sweating, nausea, vomiting and spleen enlargement. These are characteristic of an inflammatory Th1 immune response. These responses help control the replication and proliferation of the malaria parasite Plasmodium spp. in the blood. Without these control measures the malaria parasite can quickly replicate and infect numerous red blood cells leading to severe anemia and death.
Image courtesy of: http://www.nature.com/nri/journal/v4/n3/fig_tab/nri1311_F3.html
We know that in sub-Saharan Africa the prevalence of helminth and malaria infections is very high. It is very likely that numerous individuals will be infected with both helminths and malaria concurrently. These concurrent infections will change the disease progression of both diseases but we will focus on how helminths change malaria infection for the time being.
Image courtesy of: http://www.ncbi.nlm.nih.gov/pubmed/16989681
As mentioned, helminths will drive a very strong Th2 and Treg response, and suppress the Th1 response that would be the typical response in a malaria infection. Researchers have noticed as a result that there is an increase of severe malaria cases in individuals who have concurrent helminth infections, most likely due to the inability for the host to properly regulate the malaria parasites through an inflammatory Th1 response.
This is very problematic and questions our current treatment strategies. For example, we may want to tailor malaria control by administering anthelmintics to those at risk for malaria to lessen the severity of the malaria infection.
However, the severity of malaria is not the only issue that needs to be considered, the ability to administer vaccines to control for certain diseases are also affected. While we do not currently have a vaccine for malaria, several are currently in development and undergoing field-testing. Research has shown that the helminths’ ability to skew the immune system to a Th2 mediated response, can alter the host’s response to vaccines by dampening other immunological responses. This may have complex consequences for any future malaria vaccines.
A set of researchers have shown that in mice deworming (removing helminths) prior to the administration of a malaria vaccine significantly increases the effectiveness of the vaccine when the mice are administered malaria. The most likely explanation is that the removal of the helminth, stops pushing a Th2 immune response, and allows to host to react efficiently to the administered vaccine. This has very real implications in how we should approach the management of both malaria and helminths in the field. If we are able to develop an effective malaria vaccine it is likely advisable to clear patients of helminths (even if there are no clinical helminth symptoms), so that they can properly respond to vaccination.
In previous weeks we have discussed the use of helminths as a means to dampen inflammatory responses to assist people with auto-immune diseases. While these applications may seem promising there are very real, and very significant drawbacks to presence of helminths in patients, and any use as possible therapeutics must be carefully evaluated.