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  1. What is a pathogen? Are there non-infectious pathogens?

    Olivier Garraud, EFS Auvergne - Loire

    14 May 2012

    What is a pathogen? Are there non-infectious pathogens?

    Olivier Garraud1,2*, Gamal Badr3,4, Sandrine Laradi1,2, Fabrice Cognasse1,2.

    1. EA3064 Faculty of Medicine, University of Lyon, 42023 Saint-Etienne cedex 2, France
    2. Etablissement Français du Sang Auvergne-Loire, 25 boulevard Pasteur, 42023 Saint-Etienne cedex 2, France
    3. Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
    4. Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt

    In an elegant Q&A article in this journal, Pirofski and Casadevall recently presented their view of what constitutes a pathogen [1]. It is common sense that the word ¿pathogen¿ refers to a microbe, which induces pathogenicity and leads to clinical or sub-clinical (but pathological) infection in a host. Thus, this germ/microbe has an intrinsic property of virulence; however, virulence and pathogenicity are revealed only in susceptible hosts, those that are vulnerable to this type of infection, within a given context. Thus, pathogenicity can be recapitulated as an intrinsic property of the microbe and host susceptibility [2]. Infection of the host can develop grossly due to one of two situations: the microbe escapes any type of immune defense in any non-previously immunized host of the same species, or the defense capacity of the host is impaired. These situations are not mutually exclusive because certain microbes incapacitate innate and/or adaptive immune cells. General consensus exists on these topics, and previously unanswered questions, such as how the host¿s immune system can distinguish between the ¿good, the bad, and the ugly¿, with special mention of commensal microbes, have been clarified with descriptions and fine understanding of the microbiota and so-called ¿physiological inflammation¿ [3, 4].
    One can now wonder whether the concept of ¿pathogen¿ applies only and restrictively to microbes, or if it can be extended to other situations. Evidence exists that inert particles, such as metals or crystals, are detrimental to body parts, tissues, or organs, and natural products of cell metabolism, such as inflammatory factors, can also be ¿toxic¿ when in excess or because they interfere with certain conditions in the patient. These materials do not usually go by the term ¿pathogens ¿, but are named by the type of pathology they are responsible for. In this commentary, we would like to put forward the idea that foreign cells or tissues referred to as donor cells that are injected or grafted in order to treat or assist in medical or surgical treatment of a host, referred to as a recipient, may be pathogenic under circumstances that depend on both the foreign (allogeneic) donor cells and the recipient, if he/she is susceptible or vulnerable to this condition. All properties that have been acknowledged for the microbe/host tandem leading to pathogenicity can be found in, for example, transfusion [5]. A notable exception in this example is the intent to treat or assist the patient in the transfusion case, and while virulent microbes are no longer administered in patients with the intent to cure them from an unrel ated disease (as they used to be, e.g. malariatherapy). Foreign cells exhibit characteristics that may lead to unwanted effects in susceptible hosts, i.e. displaying so-called natural or acquired (post-immunization) antibodies directed at host cell surface antigens. The immune status of the host or recipient is acknowledged to matter (e.g., antigen group association, HLA-haplotype that governs antigen presentation; transfusion-related immuno-modulation [TRIM] in patients transfused on multiple occasions with incompatible blood cells and/or receiving aged blood components) [6, 7]. More complex is a situation seemingly related to the blood component itself, which can be altered during storage and emit microparticles with oxygenated lipids and pro-inflammatory (red cells, platelets) and inflammatory products (platelets, residual leukocytes) [8].
    Safety measures for collection, production, and delivery have considerably decreased discomfort, incidents, and accidents linked to cell component transfusion, but despite these sustained efforts, inflammatory conditions still persist under certain circumstances and in certain patients. Whether certain donor cells are prone to activation and secretion of inflammatory products is not known, but certain confounding pathological situations favor the occurrence of severe accidents in certain recipients. Transfusion-associated inflammation that is highly expressed certainly represents an unwanted condition; it is rare, though not exceptional, especially with platelet components [9]. Recent experimental evidence indicates that the transfusion of allogenic cells, even to an ¿as compatible as possible¿ host, induces some degree of sub-clinical inflammation comparable to what is observed in the gut in relation to commensal microbes of the microbiota, and evokes remarkably similar cells, such as monocytes and regulatory T-cells. To recapitulate, in our opinion the case of allogeneic cells strongly parallels the case of microbes displaying general characteristics of pathogenicity. This similarity is why transfusiologists usually consider at least leukocytes as pathogens whose deleterious effects in the recipient hosts are neutralized by novel pathogen inactivation processes that have mainly been made available to prevent transfusion transmitted infections but inactivate leukocytes as well [10]. The issue of the pathogenicity of certain elements present within blood products, particularly while aging, is now being questioned so novel safety measures can be implemented. Based on this argument, we wish to extend the concept of pathogen to elements other than microbes, essentially with the intent to call attention to the implementation of prevention measures.

    References :

    1. Pirofski LA, Casadevall A: Q and A What is a pathogen? A question that begs the point. BMC Biol 2012, 10:6.
    2. Suhir H, Etzioni A: The role of Toll-like receptor signaling in human immunodeficiencies. Clin Rev Allergy Immunol 2010, 38(1):11-19.
    3. Chung H, Kasper DL: Microbiota-stimulated immune mechanisms to maintain gut homeostasis. Curr Opin Immunol 2010, 22(4):455-460.
    4. Jarchum I, Pamer EG: Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol 2011, 23(3):353-360.
    5. Stroncek DF, Rebulla P: Platelet transfusions. Lancet 2007, 370(9585):427-438.
    6. Seghatchian J, Hervig T, Putter JS: Effect of pathogen inactivation on the storage lesion in red cells and platelet concentrates. Transfus Apher Sci 2011, 45(1):75-84.
    7. Shaz BH, Stowell SR, Hillyer CD: Transfusion-related acute lung injury: from bedside to bench and back. Blood 2011, 117(5):1463-1471.
    8. Morrell CN: Immunomodulatory mediators in platelet transfusion reactions. Hematology Am Soc Hematol Educ Program 2011, 2011:470-474.
    9. Semple JW, Italiano JE, Jr., Freedman J: Platelets and the immune continuum. Nat Rev Immunol 2011, 11(4):264-274.
    10. Reesink HW, Panzer S, McQuilten ZK, Wood EM, Marks DC, Wendel S, Trigo F, Biagini S, Olyntho S, Devine DV et al: Pathogen inactivation of platelet concentrates. Vox Sang 2010, 99(1):85-95.

    Competing interests

    None of the authors declare conflict of interest in relation with this comment