Lecture Notes

1 Overview and distribution of papers (PDF) In this session, we will present an overview of general concepts in immunology and describe the different effectors of the immune system. We will also introduce the two types of pathogens that we will encounter in this course, viruses and bacteria, together with the normal immune response they elicit. Then we will present an overview of how viruses and bacteria can interfere with the immune system, with an emphasis on the pathways investigated in the papers that will be discussed in class.
2 Phagocytosis (PDF) The concept of phagocytosis (engulfment of large particles by the cell membranes of immune cells) will be briefly reviewed, with an emphasis on the difference from macropinocytosis, which involves a different mechanism for the uptake of extracellular material. The two papers analyzed in this class will show how Salmonella can evade efficient phagocytosis by triggering macropinocytosis and modifying the environment of the phagosome to promote its survival. By looking at an older paper and a more recent paper, we will learn how techniques used in the field to answer similar questions have evolved over the years.
3 Toll-like receptors (TLRs) (PDF) The innate immune system can discriminate between self and a variety of pathogens through pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) recognize PAMPs and trigger an immediate inflammatory response. Initial attention focused primarily on the identification of microbially-derived ligands that stimulate mammalian TLRs and the downstream signal transduction events they elicited. Recently, several lines of evidence have emerged that TLRs are also involved in detecting viruses and initiate antiviral responses. This week the discussion will be focused on two examples of how such an antiviral immune response is elicited and how Vaccinia virus has evolved effectors to inhibit these intracellular signaling cascades to promote virulence.
4 The proteasome and ubiquitin (PDF) Proteins that are no longer needed or do not properly function are destroyed by the proteasome. These proteins are targeted for such degradation by the post-translational attachment of ubiquitin. To prevent degradation of proteins that are essential for the functioning of pathogens, bugs have developed clever ways to remove the ubiquitin tag from these essential proteins with deubiquinating enzymes (DUBs). This then results in their rescue and restores their original function. This week we will discuss tools that have been developed recently for the identification of DUBs and their possible role in immune evasion by Herpes simplex virus (HSV) and the bacterial pathogen Yersinia.
5 Major histocompatibility (MHC) class I antigen presentation (PDF) The classical pathway of endogenous antigen presentation will be reviewed briefly followed by a discussion of how Human cytomegalovirus (HCMV) can trigger down-regulation of MHC class I at the cell surface and hide from T cell killing. The first paper shows how an HCMV gene product was found to target MHC class I for degradation in the cytosol. The second paper identifies the cellular machinery used by the virus to reach its goal. These papers highlight the usefulness of studying pathogens to understand normal cellular processes.
6 Major histocompatiblity (MHC) class II antigen presentation (PDF) Infection of CD4+ T cells with the Human immunodeficiency virus (HIV) leads to the demise of the immune system and the clinical manifestation of AIDS. Paradoxically, the very receptor that serves as point of entry for HIV, CD4, is surface down-regulated upon infection. In the first paper that will be discussed, the role of the HIV-derived nef gene in this observation is investigated. In the second paper, the nef gene product is shown to interact with another element of the MHC class II Ag presentation pathway: The Invariant Chain. We will examine how HIV could benefit from adapting intracellular trafficking of these molecules through Nef.
7 Cytokines (PDF) Cytokines are short-lived small molecules that can influence the outcome of an immune response by activating certain types of cells or acting as chemoattractants to direct immune cells to a site of infection. In this class, we will see how viruses can use the cytokine system to their advantage with two different strategies. First, we will see how Kaposi Sarcoma-Associated Herpes virus secrete chemokine-like molecules that can counteract the effect of endogenous cytokines and trick our immune cells into modifying their response. Then, we will see how HIV uses a chemokine receptor to anchor itself and eventually penetrate the host cell.
8 Programmed cell death (PDF) Another way that cells can interfere with viral or bacterial infection is to die by apoptosis (programmed cell death) and destroy the environment in which the pathogen thrives. In this class, we will see how viruses such as Mixoma virus and Epstein Barr virus (EBV) can express proteins that block apoptosis and allow them to survive. We will see that such mechanisms usually target the mitochondria, which is a key organelle in the process of apoptosis. We will also find out that this strategy can be associated with virally-induced cancers, such as the Burkitt's B cell lymphoma caused by EBV.
9 Molecular mimicry (PDF) The immune system sends cytotoxic T-cells on a mission to search and destroy those cells that present pathogen-derived antigens on their class I major histocompatibility complexes. It therefore makes sense for pathogens to interfere with the processing and presentation of antigens associated with MHC complexes as well as the expression of these complexes on the cell surface. Immune evasion of this sort is countered by natural killer (NK) cells, which sense a reduction in surface MHC and move in for the kill. Today we will learn how cytomegalovirus diverts the NK-cell mediated destruction by the expression of surrogate MHC molecules that interact with NK inhibitory receptors.
10 Antimicrobial peptides: Innate immunity effectors (PDF) Cationic antimicrobial peptides (CAPs) have the capacity to nonspecifically disrupt membrane integrity in a variety of microorganisms, ultimately leading to cell death. This molecular weaponry is used by bacteria in their competition for living space and sustenance and also is used by the innate immune systems of higher organisms. In this session we will discuss how Salmonella typhimurium senses the presence of CAPs and reacts by initiating a signal-transduction cascade that leads to transcription of virulence gene-products to promote bacterial infection. On the other hand, we will also see that Bordetella bronchiseptica can attenuate CAP gene expression, thus effecting evasion of the innate immune system.
11 Oral presentation Students will take approximately 20 minutes, depending on the number of students either alone or in teams of two, to present a paper that will be discussed afterwards. This paper needs to be pre-approved by the instructors on the Session 9 at the latest. Students who have selected their own paper are expected to bring hard-copies of that paper and distribute it among all participants of the course the week before (Session 10). These hard-copies will serve only as reference material for the other students, and only the student who gives the oral presentation is expected to have studied the respective paper throughout.
12 Oral presentation and general discussion

Additional time will be available for oral presentations in the same format as Session 11 should that be required.

Finally, all aspects of the normal immune response towards viruses and bacteria and their respective counterattacks that have been highlighted in the class will be reviewed. We will then engage in a group discussion on the usefulness of studying pathogens to learn about mammalian cell biology and immunology.