| 1. |
- Andersson, Anna-Maria, 1990-
(författare)
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Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) still remains a big threat today, being the leading cause of death by a single infectious agent. The TB epidemic is fueled by HIV along with the increasing drug-resistance which prolongs the already long treatment duration and decreases the success rate for curing TB. In most cases an infection results in latency but HIV patients have a 20-30 times higher risk of developing active TB. There are around 36.9 million people living with HIV globally, with the highest burden in Africa. Although there are effective treatments against the disease, there is no cure for AIDS and the availability of the lifelong treatment is limited in low-income countries were the burden is highest. HIV infection causes an immunodeficiency characterized by the progressive loss of CD4 T cells which increases the risk of opportunistic infections, and infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb spreads through aerosols from one person with active tuberculosis to a healthy person. Upon inhalation the bacteria are phagocytosed by alveolar macrophages that secrete cytokines and chemokines to recruit more cells, such as dendritic cells, macrophages and lymphocytes, leading to the formation of a granuloma. During a single TB infection the bacteria are usually contained within the granuloma, but HIV can disrupt the stable granuloma, causing a rupture and dissemination of Mtb. This inflammatory site is also beneficial to HIV since it promotes replication of the virus within infected cells. HIV and Mtb are two successful intracellular pathogens able to avoid immune defense mechanisms both of the innate and adaptive immunity in order to persist and replicate. Their virulence factors can manipulate or inhibit cell signaling, phagosome maturation, autophagy, ROS production, apoptosis and antigen presentation, to promote survival. Boosting of immune defenses with host-directed therapies (HDT) has been proposed as a treatment strategy against TB, either alone or adjunctive to the current regimen.In this thesis, ways to boost the innate immune responses in Mtb and HIV coinfected macrophages were investigated, along with studies of the effect of HIV on Mtb antigen presentation in coinfected dendritic cells. The initial hypothesis was that autophagy induction through inhibition of mammalian target of rapamycin (mTOR) could suppress Mtb growth in HIV coinfected macrophages. However, during a low grade infection, autophagy induction increased Mtb replication due to a decreased autophagic flux and acidification of Mtb phagosomes. A general autophagic flux was induced, although not localized to the Mtb phagosomes, thus not inducing a xenophagy (autophagy of intracellular pathogens). Other ways of inducing autophagy or boosting the response in coinfected macrophages might be more beneficial and therefore the effect of efferocytosis was investigated. Uptake of apoptotic neutrophils by coinfected macrophages did not induce autophagy but enhanced the control of Mtb by other means. Upon efferocytosis, the macrophages acquired active myeloperoxidase (MPO) from the neutrophils that suppressed Mtb growth. The coinfected macrophages also produced more ROS after efferocytosis. The inhibition of Mtb growth could thus be mediated by MPO and the increased ROS production either directly or indirectly.The possibility to boost the innate immunity could prove to be important during an HIV coinfection, when the adaptive immunity is deficient. In addition to the well-known decline in CD4 T cells during the course of HIV progression, we found that HIV infection of dendritic cells inhibited antigen presentation by suppressing the expression of HLA-DR and co-stimulatory molecules on coinfected dendritic cells. Furthermore, HIV reduced secretion of pro-inflammatory cytokines and suppressed antigen processing through inhibition of autophagy. This impaired antigen presentation in coinfected dendritic cells resulted in a decreased activation and response of Mtb-specific CD4 T cells.In conclusion, this thesis shows how HIV can manipulate antigen presentation in Mtb coinfected dendritic cells and subsequently inhibit the adaptive immune response. It also contributes to insights on how efferocytosis of apoptotic neutrophils can boost the innate immune responses during coinfection. Lastly, autophagy induction through mTOR inhibition does not enhance protection against TB. Induction of autophagy should therefore be handled with care, particularly during HIV coinfection.
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| 2. |
- Svanberg, Cecilia, 1991-
(författare)
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HIV-1 Exploitation of Dendritic Cell Functionality and Initial Responses in Mucosal Tissues : Elucidation of Influence of HIV-1 Complement Opsonization, and HIV-1-HSV-2 Co-infection
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human immunodeficiency virus (HIV)-1 is transmitted between individuals via sexual intercourse or via blood products. To date there are 38 million people living with chronic HIV infection and around 1.5 million yearly acquire a new infection. HIV is known to have detrimental effects on the immune system and its cell function and leads to the development of acquired immune deficiency syndrome (AIDS). AIDS is characterized by opportunistic infections often fatal to the individual. Mucosal tissues, which are the main site of HIV-1 infection, consist of a complex network of different cell types building up a barrier against the outside world. In the mucosa there are multiple immune cells and one of them is the dendritic cells (DCs), a professional antigen presenting cell needed for priming of adaptive T cell responses. DCs are rarely productively infected with HIV-1 but the virus can modulate the DC phenotype and function by mere exposure to the virus. There are many factors that influence viral transmission including prevalent inflammatory conditions or infections in the genital tract. For instance, a newly acquired herpes simplex virus-2 (HSV-2) infection increases the risk of transmission at HIV-1 exposure by four times. A vital part of the innate immune defense is the complement system, which consists of proteins found in all body fluids. Normally during complement activation, it leads to lysis of pathogens, but HIV-1 can evade this process. This is achieved by the incorporated complement regulatory proteins in the viral plasma membrane leading to accumulation of opsonizing complement fragments on the HIV-1 particles. Our aim with these studies was to deepen the understanding of the HIV-1 exploitation of DC function and elucidate the initial effects exposure and establishment of HIV-1 infection has on the mucosal tissues and immune cells. In addition, we aimed to elucidate the effects HSV-2 exerts on the HIV-1-infection of DCs and how viral complement opsonization affects the viral infection and activation of immune responses. In Paper I we found that coinfection of monocyte derived DCs (MDDCs) with HIV-1 and HSV-2 decreases the amount of the HIV-1 restriction factors SAMHD1 and TREX1 in MDDCs, leading to increased productive HIV-1 infection. In Paper II and III we found that HIV-1 utilizes the complement system to induce higher productive infection of the colorectal and cervical mucosal DCs. The different forms of HIV, free or complement opsonized, had distinct effects on the immune responses and T cell phenotypes in the tissues, all in favor of HIV-1 establishment and productive infection. In Paper IV, HIV-1 exposed DCs triggered after crosstalk with suppressive T cells a prolonged type I interferon response and an upregulation of coinhibitory molecules on the DCs. The findings in this thesis add to the knowledge of HIV-1 early transmission events, how co-infection modulates DC function, and how the presence of HIV-1 affects the priming of adaptive immune responses.
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| 3. |
- Ellegård, Rada, 1985-
(författare)
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Effects of Complement Opsonization of HIV on Dendritic Cells : and Implications for the Immune Response
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.
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