Pathogen Mode of Entry Has a Significant Effect On Host Adaptation

In order for us to properly understand the diseases that make us sick we must examine the entire mechanism the pathogen (disease causing agent) uses to invade our bodies. Much experimental work has been done to understand the pathogen mechanism once it has generated an immune response in the body, however one of the most important steps in the mechanism, which hasn’t really been experimentally studied, is the mode of entry. There are two major ways that a pathogen can enter the body, either through ingestion (orally) or systematically (a prick or needle). When a pathogen enters the body systematically it bypasses much of the innate physiological and anatomical barriers that prevent pathogen entry, like our skin, sweat, oils and mucus we secrete. In contrast, a pathogen must overcome many more barriers when entering the body orally, for instance saliva.

It has been shown in a recent experiment that the path of pathogen entry affects the rate at which the pathogen is eliminated and the way that it responds to the same type of pathogen. In the experiment equal amounts of both male and female Drosophila melanogaster flies were administered with one of two treatments of P. entomophila bacterial strain. Half the male and female flies were introduced to P. entomophila orally (BactOral), whereby food plates were coated in the bacterial strain. The other half of male and female flies was injected in the thoracic (area where the legs and wings attach) region with P. entomophilia (BactSys). Controls for both the injection (ContSys) and food treatments (ContOral) were also observed in the experiment. The mortality of the flies was measured for at least 10 days. It was found that the survival rate of the flies was much higher when the bacterial strain was introduced orally. The evolution of resistance to the particular bacterial strain also developed much faster when P. entomophilia was introduced orally.

These results reaffirm the theoretical notion that oral pathogens have to overcome more physical barriers in order for them to enter the body cavity. This is in contrast to a systematic infection because the physical barriers, like the skin have already been bypassed and the bacteria have been directly injected into the body cavity. So when a pathogen enters systematically the body must rely on other, more active ways of identifying and eliminating the invader, namely through members of the immune system that belong to the adaptive (more-specific) response like plasmatocytes. These more complex and specific ways of eliminating the invader are slower to act because B cells must be activated to produce antibodies, that than must find the pathogen and kill it, whereas much of the pathogen that was introduced to the mice orally didn’t really require the activation of the adaptive immune response. It only had to rely on the innate (more general) immune response and physiologic barriers that were already in place like the mucosa layers of the respiratory and gastrointestinal tracts to prevent pathogen entry into the body cavity. Since these defenses are already localized to the site of pathogen entry and need no further activation, the immune response is much faster when the pathogen is administered orally rather than systematically.

Hey Virus: Replicate Here!

The innate immune system, that part of the immune system that responds to non-specific signs of pathogen infection, faces a quandary when mounting a response against a pathogen. On one hand, it must limit the replication of the pathogen to prevent spread throughout the body. On the other, it must facilitate the development of a specific adaptive immune response, which can clear the pathogen from the body and lead to immunologic memory. It might seem like both of these are reasonable tasks, but the quandary lies in the fact that the adaptive immune system must be activated by a certain amount of antigen (proteins derived from the pathogen that can be effectively targeted by the immune system) in order to elicit an effective response. Low levels of antigen lead to weak responses, whereas high amounts of antigen induce strong responses. Thus, if the innate immune system does the first part of its job too well and largely prevents virus replication, there will not be enough viral antigen present to stimulate a robust adaptive response. So how does the immune system get around this predicament? A new paper in Nature Immunology by Nadine Honke and her colleagues sheds some light on this question (1).

            The major weapons in the innate immune system’s arsenal are small, secreted proteins called interferons. When cells in the body detect a pathogen, they produce interferons, which alert the surrounding cells to the impending danger. These “warning flags” bind to interferon receptors found on the surface of all cells, and induce the expression of a large number of genes, termed interferon stimulated genes (ISGs), which can combat the pathogen through various means. Interferons also initiate mechanisms that facilitate the adaptive immune response, by increasing the presentation of specific antigens to the T cells and B cells that comprise the adaptive immune system. To effectively stimulate T cells, however, requires a sufficient dose of antigen: prior studies have indicated that over 20,000 copies of the antigen are required for an antigen-presenting cell to induce a robust T cell response (2). So, how can the innate immune system effectively prevent the spread of a pathogen while still providing enough “grist” to be presented to naïve T cells? Honke et al began to answer this by examining a particular subset of innate immune cells, metallophilic macrophages.

Natural Killing and Adaptive Immunity: the role of NK cells in CD8+ T cell differentiation

In the human immune response, an encounter with a pathogen results in the rapid division of immune cells which neutralize and kill viruses, bacteria and parasites. While this rapid increase in the number of immune cells in the body is necessary for a robust and effective immune response, once the pathogen has been cleared it is essential that immune cell levels be brought back down to normal. CD8⁺ T cells, also known as cytotoxic T lymphocytes (CTLs), are one type of immune cell that follows this pattern of expansion and contraction. In the presence of an antigen, CD8⁺ T cells specific for that antigen divide rapidly, seeking out and killing infected cells and pathogens. When the threat has been cleared, high levels of CD8⁺ T cells specific for a single antigen are no longer necessary, and the majority of CD8⁺ T cells die by apoptosis. The surviving CD8⁺ T cells differentiate into memory T cells, allowing the body to respond more quickly and effectively the next time it encounters the same antigen. This process is essential for maintaining immunity to diseases; the memory T cells and B cells produced after an initial exposure are the reason that, for example, you only get chicken pox once. Similarly, memory T cells and B cells enable the body to prevent infection by pathogens against which it has been vaccinated.

In a paper published in the Journal of Immunology just this week, Soderquest, et al. examine the relationship between CD8+ s and natural killer cells (NK cells) after an infection has been cleared. NK cells are an important part of innate immunity – that is, the rapid and general immune response that includes both physical barriers to infection (i.e. the skin and mucosa) and non-specific killing cells like the NK cell. During the innate immune response, NK cells identify and kill cells that are either infected with viruses or are tumorigenic. Apart from their role in the innate immune response, recent studies have shown that NK cells play an important part in the development of the more specific adaptive immune response, particularly in promoting the differentiation of CD4⁺ “helper” T cells (Th cells). In investigating the relationship between CD8⁺ T cells and NK cells, Soderquest et al. focused on the NKG2D pathway of NK cell killing. NKG2D is a protein expressed on the surface of NK cells that binds to NKG2D ligand (NKG2DL) on a target cell and induces apoptosis via the perforin/granzyme pathway. The authors of this article hypothesized that NK cells influence the development of CD8⁺ T cell-mediated adaptive immunity by killing activated CD8⁺ T cells via the NKG2D/perforin pathway.