Respiratory infections: do we ever recover?

Abstract

Although the outcome of respiratory infection alters with age, nutritional status, and immunologic competence, there is a growing body of evidence that we all develop a unique but subtle inflammatory profile. This uniqueness is determined by the sequence of infections or antigenic insults encountered that permanently mold our lungs through experience. This experience and learning process forms the basis of immunologic memory that is attributed to the acquired immune system. But what happens if the pathogen is not homologous to any preceding it? In the absence of cross-specific acquired immunity, one would expect a response similar to that of a subject who had never been infected with anything before. It is now clear that this is not the case. Prior inflammation in the respiratory tract alters immunity and pathology to subsequent infections even when they are antigenically distinct. Furthermore, the influence of the first infection is long lasting, not dependent on the presence of T and B cells, and effective against disparate pathogen combinations. We have used the term "innate imprinting" to explain this phenomenon, although innate education may be a closer description. This educational process, by sequential waves of infection, may be beneficial, as shown for successive viral infections, or significantly worse, as illustrated by the increased susceptibly to life-threatening bacterial pneumonia in patients infected with seasonal and pandemic influenza. We now examine what these long-term changes involve, the likely cell populations affected, and what this means to those studying inflammatory disorders in the lung.

Figure 1.

The outcome of respiratory infection depends on whether immunologic memory exists. In a naive host, infection induces a highly inflammatory microenvironment, and antigen-presenting cells loaded with antigen track to the draining lymph node where they activate CD4⁺ and CD8⁺ T cells (A). Further inflammatory cytokines, produced due to unchecked viral replication, recruit a large inflammatory infiltrate (B) that eventually occludes the airways. Memory B and T cells migrate to the spleen (C). In hosts with cross-reactive T and B cells, however, antigen-specific cell migration occurs very quickly (D). Viral replication is rapidly controlled leading to less inflammation (E). MLN = mediastinal lymph node.

Figure 2.

Collagen deposition during Cryptococcus neoformans infection. Mice were infected intranasally with C. neoformans and lung inflated and fixed in formalin 12 days later. Paraffin-embedded sections were stained with periodic acid Schiff, and collagen deposition (blue) and cellular infiltrate (brown) identified by light microscopy. Original magnification, × 200.

Figure 3.

The influence of infection on memory T-cell repertoires in monozygotic twins. Despite the genetic similarities, established memory T-cell pools will vary depending on the infections encountered, the degree of attrition that may be affected by the severity of infection, and private T-cell specificities. In this rather simplified schematic in (A), twin 1 becomes infected with virus 1, whereas twin 2 does not. Twin 1 will therefore have resident immune memory to virus 1. In (B), both twins experience infection 2, but the response to this in twin 1 is less because of innate adapted influences from the first infection. Furthermore, in twin 2, homeostatic suppression of T-cell expansion may be less. In (C), both twins experience infection 3, which reduces the memory T-cell pool to infection 1 (in twin 1) and infection 2 (in both twins) due to attrition (see text). In (D), infection 4 gives rise to immunologic memory in both twins but also an expansion of memory cells to infection, one due to cross-reactive epitopes between viruses 1 and 4. (E) The heterogeneity in the memory T-cell pools after multiple infections in identical twins is shown. This heterogeneity and influence of previous infections could also easily extend to innate immunity.