Defining paradigms of intracellular survival through the study of tick-borne Anaplasma
Lead Research Organisation:
University of Bristol
Department Name: Faculty of Health Sciences
Abstract
Bacteria have evolved to survive in diverse and hostile environments, including within the cells of other organisms. This presents unique challenges as host cells need to be restructured to accommodate these microbes and host organisms possess defence mechanisms to eliminate invaders. To overcome these challenges, some bacteria produce specialised proteins called effectors that are injected into the host cell and disrupt normal cellular processes by binding or modifying host proteins and cellular components. This enables bacteria to evade host defences, enter the cell, and reshape its environment.
The tick-borne pathogens, Anaplasma, are obligate intracellular bacteria - they are so well adapted to life inside host cells that this is the only place they can survive. They spread by tick bites to a wide range of different vertebrate hosts, including humans, where they cause anaplasmosis, a serious disease of livestock that is estimated to cost the global cattle industry billions of dollars per annum. Considering they are a significant global problem for human and animal health, and economies, Anaplasma are surprisingly under-studied and only a handful of their effector proteins have been the focus of research, probably because Anaplasma are very difficult to study through classic genetic approaches. Since effectors are essential for Anaplasma infection, it is crucial that we determine how they function so that we can find new ways to combat these pathogens.
In this Fellowship I will use a multi-disciplinary approach to overcome the obstacles associated with Anaplasma study and uncover how their effectors enable intracellular survival. I have already determined that some Anaplasma effectors target a large number of host proteins which are responsible for controlling a plethora of cellular functions. Intriguingly, many of these functions also happen to be disrupted during Anaplasma infection and are important aspects of the disease, anaplasmosis. Using microscopy, I have also identified that some of these effectors redirect host signalling complexes to intracellular Anaplasma, likely playing a role in making a favourable environment for them to survive and replicate. These discoveries provide a strong indication that effectors have a central roles in pathogenesis and enabling intracellular survival of Anaplasma.
Building on this initial data I will determine:
i) The identities of effector targets and how their activities are orchestrated within host cells throughout the Anaplasma infective cycle.
ii) The structural basis for Anaplasma effectors to bind host targets and how these interactions influence the biochemical activities of these targets.
iii) Which aspects of host biology are influenced by effectors to enable intracellular survival and how these activities relate to their structures and interactions.
The results from this work will reveal molecular bases for Anaplasma survival inside host cells, how they cause disease, and identify new avenues to treat anaplasmosis. Since the effector proteins studied here have similarity to those found in a wide range of different obligate intracellular microbes including; close relatives to Anaplasma, the Rickettsiales, which includes many important tick and vector-borne pathogens; more distantly bacteria, such as Chlamydia; and unrelated microbes, such as DNA viruses; it is likely that our discoveries will have broad relevance, revealing generalised intracellular survival strategies. In addition, Anaplasma effectors represent a molecular toolkit for dissecting eukaryotic protein functions and cell biology, and there are clues that they might function in both, tick and vertebrate hosts. As such, this fellowship aims to address tick-borne disease, principles in intracellular survival, and fundamental cell biology.
The tick-borne pathogens, Anaplasma, are obligate intracellular bacteria - they are so well adapted to life inside host cells that this is the only place they can survive. They spread by tick bites to a wide range of different vertebrate hosts, including humans, where they cause anaplasmosis, a serious disease of livestock that is estimated to cost the global cattle industry billions of dollars per annum. Considering they are a significant global problem for human and animal health, and economies, Anaplasma are surprisingly under-studied and only a handful of their effector proteins have been the focus of research, probably because Anaplasma are very difficult to study through classic genetic approaches. Since effectors are essential for Anaplasma infection, it is crucial that we determine how they function so that we can find new ways to combat these pathogens.
In this Fellowship I will use a multi-disciplinary approach to overcome the obstacles associated with Anaplasma study and uncover how their effectors enable intracellular survival. I have already determined that some Anaplasma effectors target a large number of host proteins which are responsible for controlling a plethora of cellular functions. Intriguingly, many of these functions also happen to be disrupted during Anaplasma infection and are important aspects of the disease, anaplasmosis. Using microscopy, I have also identified that some of these effectors redirect host signalling complexes to intracellular Anaplasma, likely playing a role in making a favourable environment for them to survive and replicate. These discoveries provide a strong indication that effectors have a central roles in pathogenesis and enabling intracellular survival of Anaplasma.
Building on this initial data I will determine:
i) The identities of effector targets and how their activities are orchestrated within host cells throughout the Anaplasma infective cycle.
ii) The structural basis for Anaplasma effectors to bind host targets and how these interactions influence the biochemical activities of these targets.
iii) Which aspects of host biology are influenced by effectors to enable intracellular survival and how these activities relate to their structures and interactions.
The results from this work will reveal molecular bases for Anaplasma survival inside host cells, how they cause disease, and identify new avenues to treat anaplasmosis. Since the effector proteins studied here have similarity to those found in a wide range of different obligate intracellular microbes including; close relatives to Anaplasma, the Rickettsiales, which includes many important tick and vector-borne pathogens; more distantly bacteria, such as Chlamydia; and unrelated microbes, such as DNA viruses; it is likely that our discoveries will have broad relevance, revealing generalised intracellular survival strategies. In addition, Anaplasma effectors represent a molecular toolkit for dissecting eukaryotic protein functions and cell biology, and there are clues that they might function in both, tick and vertebrate hosts. As such, this fellowship aims to address tick-borne disease, principles in intracellular survival, and fundamental cell biology.
