Microbial Pathophysiology and Opportunistic Infections: Surprises Ahead

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  2. Microbial Pathophysiology and Opportunistic Infections: Surprises Ahead

CITATION Greenblatt MB, Aliprantis A, Hu B, Glimcher LH. Calcineurin regulates innate antifungal immunity in neutrophils. J Exp Med 2010; 207: 923–931.

CITATION Iannacone M, Moseman ES, Tonti E, et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 2010; 465: 1079–1083.


Opportunisitic infections (OIs) are frequent and serious complications of organ transplants and all immunosuppressive regimens and drugs. OIs are generally considered to be a consequence of the specific effects of the immunosuppression on the immune system, particularly the T and B cells, not least because many immunosuppressive drugs are targeted to these lymphocytes. The general approach to OIs has not changed in more than 20 years, even though molecular testing is available for pathogens (providing more rapid and specific diagnoses), advanced imaging techniques are able to pinpoint minute lesions and many types of antibiotics are at hand. Management invariably consists of reducing or stopping immunosuppression, along with administration of antibiotics. While this is frequently successful, cases of uncontrolled infection are seen, and/or reduction of immunosuppression results in rejection and organ damage or loss. To improve these outcomes, it is necessary both to enhance the diagnostic and antimicrobial armamentarium, and to gain a more detailed and nuanced understanding of the immune response to specific pathogens.

Pathogenesis studies are now giving us a glimpse into the functions of the immune system that impact on OI. Greenblatt and colleagues studied disseminated Candida albicans infection in a mouse model (Fig. 1). Surprisingly, immunity was not determined by the adaptive immune system of T and B cells, but rather by innate immunity. Specifically, neutrophils were responsible for control of infection and survival. Neutrophils recognized fungal cell wall β(1,3)-glucans via the dectin-1 receptor, which then relied on downstream calcineurin B-dependent signaling to activate antifungal responses. Mice deficient in neutrophil calcineurin B were unable to control infection and succumbed to overwhelming sepsis within a few days, even though they had an otherwise intact immune system. These findings suggest that, at least for fungal infections, the key to treatment is the enhancement of neutrophil function, not only through immunosuppressive withdrawal, but also perhaps through other modalities, such as administration of granulocyte colony-stimulating factor (G-CSF) or other adjuvants. These findings suggest why it may be possible clinically to have an uncontrolled fungal infection (neutrophil dysfunction), while the system simultaneously rejects an organ (T- and B-cell competence).


Figure 1. Cyclosprin A (CsA) suppresses innate resistance to C. albicans infection. (A) Survival of C. albicans–infected mice. Rag2-/- or wild-type (WT) control mice were infected with C. albicans yeasts and treated daily with 200 mg/kg CsA or vehicle control. p < 0.0001 by log-rank test comparing CsA-treated with vehicle-treated groups. (B) Mice were infected as in A, and histological analysis of the kidneys was performed 4 d after infection. C. albicans organisms were visualized by PAS stain (purple, arrow). (C) CsA- or vehicletreated Rag2-/- or WT mice were infected with C. albicans as in A. Homogenates of the kidney were made 4 d after infection, and C. albicans was quantitated by serial dilution and colony counting. p < 0.0001 by comparing either CsA-treated group with the corresponding vehicletreated group.

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Iannocone and colleagues studied the response to vesicular stomatitis virus (VSV), a relative of rabies virus, in a murine model. Subcutaneous injection of virus, similar to its transmission by an insect bite, resulted in virus localizing to macrophages of the subcapsular sinus of the lymph node (LN). The macrophages produced type I interferon in response to infection, and recruited plasmacytoid dendritic cells that produced more type I interferon. The type I interferon then acted on both hematopoietic and stromal cells of the LN to clear the virus and eradicate infection. If subcapsular sinus macrophages were depleted, then the virus infected the peripheral nerves of the LN, resulting in an ascending neuronal infection and central nervous system viral replication, with paralysis and death within 7 to 10 days. Innate, and not adaptive, immunity was responsible for control of a lethal neurotropic pathogen. Proper anatomic arrangement of the LN and the cells within the LN was crucial for the right immune response at the right time.

CsA suppresses innate resistance to C. albicans infection.

The implications for clinical studies and management of these two reports are that the innate as well as the adaptive immune system is important to control OIs. Local, anatomically restricted immune events are key aspects of protective responses, so that assay of peripheral blood leukocytes is not mechanistically or therapeutically revealing. Lastly, we may already have additional approaches for treating OI through readily available, Food and Drug Administration-approved CSFs that are known to enhance myeloid cell numbers and function.