Pathogenesis –- literally how disease (pathos) begins (genesis) or develops –- is a broad, important area of research encompassing both basic and clinical sciences. Disease can arise from pathogens that secrete toxins, from dysregulation of the immune system or simply from aging. Far more commonly, pathogenesis occurs as a consequence of complex interactions between an infecting pathogen and the immune system. In a recent editorial, we anticipated more submissions dealing with the pathogenesis of disease, given the greater emphasis on 'translational' research (Nature Immunology 6, 637 (2005)). Simplistically, 'pathogenesis of infection' defines the way that a given pathogen influences a host's immune system. But how one understands the interaction between pathogen and host can differ considerably depending whether one is interested more in the pathogen or the immune system.
The interaction between infectious agents and the immune system can be divided into several discrete phases that differ depending on the perspective. For the pathogen, this involves inoculation into a receptive host milieu, successful initial infection of 'target' cells and replication in suitable host cells. For the host, this series of events includes initial 'recognition' of infection by sentinel host immune cells, amplification of innate immune response and, finally, adaptive immune responses that eliminate the pathogen. In actuality, a plethora of pathogens and multigenic immune systems interact. The simple dichotomy described above is complicated because neither pathogen nor host are the same each time they encounter each other and because pathogen and host rarely influence one another in a constant way throughout the course of an infection. The human immunodeficiency virus infecting someone in Bangkok is not the same virus infecting someone in Baltimore, and two people in Bangkok and Baltimore are not likely to express the same set of immune genes (such as natural killer receptors and major histocompatibility complex receptors). Pathogen-host interactions, in other words, can often be more dynamic than stable from the perspective of both pathogen and host.
From the perspective of pathogen, many variables can considerably alter immune responses. A virus that replicates with a high mutation rate such as LCMV or influenza, for example, produces progeny that potentially can interact with the immune system differently over time. Similarly, a virus that expresses an immune modulator, such as a chemokine antagonist, can express more or less of the modulator proportional to its replication rate, which can significantly alter the impact of the immune response. Or consider a hypothetical case of two strains of a single virus that differ by only a single amino acid which correlates with increased acute replication and chronicity (clearance of the virus takes much longer) for one. If the two strains of virus are compared for their capacity to stimulate CD8+ memory T cells after infection by counting lymphocytes in the spleen and draining lymph nodes the conclusions drawn would be at best incomplete without taking into account the possibility, caused by the single amino acid difference, of altered target cell tropism, altered interaction of a viral protein with host factors or altered expression of a key virulence factor. Because pathogens can present ever-changing properties to the immune system, they are rarely merely 'antigen delivery systems'.
From the perspective of the host, variables can likewise influence the lifecycle of pathogens. As but one example, whether the transcription factor STAT1 is expressed in the host determines which cells are infected and how much replication occurs. Viruses such as poxvirus myxoma virus and influenza virus, for instance, produce widely increased amounts of virus in the absence of STAT1, altering dramatically the immune responses that ensue. Host effects can be even more subtle. The role of, say, CD8+ T cells in the control of a pathogen in wild-type studied by depleting CD8+ T cells may have consequences on the tropism, replication rate (and therefore probability of mutation) or virulence due to infection of a new host niche that would not otherwise be available when CD8+ T cells are present. Pathogenesis can thus be dramatically influenced by host variability.
Science lore includes the old saw about the dispute between geneticists and biochemists on the power of yeast genetics versus biochemical studies to determine protein function. An analogous debate might be said to exist between immunologists who study pathogens and pathologists who study the immune system. Is it more important to study how many T cells or how many virus particles are present after a given time during infection?
Of course, the dichotomy itself belies a distortion of the fact that the two 'sides' are complementary. A sophisticated approach to investigating the pathogenesis of infection takes into account both parts of the equation. Both pathogen and host are complex systems that dynamically affect each other. Immune responses to pathogens are greatly determined by the variable properties of pathogens (such as changing antigenic determinants, replicative rates, tropism and so on) that stimulate them, which then in turn can affect the life cycle of the pathogen. Both pathologists interested in immunology and immunologists interested in pathogens should bear that in mind.