Host defense pathways: role of redundancy and compensation in infectious disease phenotypes

Abstract

Innate host defense pathways consist of microbial sensors, their signaling pathways, and the antimicrobial effector mechanisms. Several classes of host defense pathways are currently known, each comprising several pattern-recognition receptors that detect different types of pathogens. These pathways interact with one another in a variety of ways that can be categorized into cooperation, complementation, and compensation. Understanding the principles of these interactions is important for better understanding of host defense mechanisms, as well as for correct interpretation of immunodeficient phenotypes.

Figure 1. Different types of host pathway interactions

There are three different types of host pathway interactions: cooperation, complementation and compensation. A. Cooperating pathways induce the same effector mechanism more efficiently when engaged simultaneously. B. Complementing pathways induce distinct effector mechanisms (EM1 and EM2), which complement each other to form one functional unit. C. Compensation between two pathways occurs when one pathway is deficient and the other intact. Compensation can take place at the level of sensors (panel C top), or at the level of effectors (panel C, bottom). P – pathogens, A and B – microbial sensors, EM – effector mechanisms.

Figure 2. Compensation between host defense pathways and its role in infectious disease phenotypes

Defect in pathways A can be compensated by pathway B in the case of pathogen Px (Panel A), but not in the case of pathogen Py (panel B). Defect in EM1 can be compensated by EM2 if EM2 is sufficient to provide protection against pathogen Px (panel C). If EM2 is not sufficient to protect against Py, then EM2 will not compensate for EM1 deficiency (panel D). Solid lines: intact pathways, dashed lines: inactive pathways. Pathway deficiency can result from either mutations, or due to pathogen evasion.

Figure 3. Compensatory enhancement of host defense pathways can result in immunopathology

If more than one pathway is induced by a given infection, they can provide optimal protection with minimal immunopathology, because they do not have to be induced to a maximal level (panel A). If one pathway is deficient, the intact pathway will have to be induced to a higher level, thus increasing the potential for tissue damage.

Figure 4

‘Redundancy’ in host defense pathways is conditional on the nature of infection Pathways B is ‘redundant’ when the host is exposed to pathogen Px, but non-redundant when the host is exposed to pathogen Py. Pathways A and B are redundant with regards to the common function (activation of EM1), but non-redundant with regards to activation of EM2. Thus, conclusion of ‘redundancy’ can be affected by both the exposure rates of Px and Py, and by the ‘read-out’ (whether EM2 activation is measured or not).