A diversity of living organisms has developed the ability to live within our bodies. The broad classes of these include:

• Viruses, small particles that enclose a viral genome that must reproduce within cells.
• Bacteria, simple cells that can often divide rapidly.
• Fungi, more complex cells or branching strands of cells.
• Parasites, a broad term for organisms that invade our body that are not any of the above classes. They can include single-cell ‘protists’, and parasitic animals such as parasitic worms, and parasitic mites.

Organisms that are only visible using a microscope, such as viruses, bacteria and many fungi and single cell parasites, are often called ‘microbes’.

Infections can occur in many different parts of our body. Some organisms, such as the scabies mite, invade only a few millimetres into the outer layers of our skin. Viruses can only grow and reproduce within cells.

Some bacteria, fungi and parasites also grow within cells. Others can live within certain tissues in our body, or in cavities such as our lungs or mouth. Some diseases can occur without direct contact with the microbe, such as illness caused by toxins released by bacteria into foods.

There are many different ways that infectious agents make us sick. These include:

• Damaging cells or tissues within our body directly, such as a virus killing its host cell.
• Secreting toxins that damage cells.
• Forcing cells to behave abnormally, such as dividing uncontrollably.
• Competing for nutrients or other resources with our own cells.
• Physically obstructing the normal function of an organ.
• Triggering harmful immune responses or inflammation.

The immune response is critical to prevent infections spreading. People with immunodeficiencies may not mount an appropriate immune response and can suffer overwhelming illness from microbes that normally cause mild or no infection.

The symptoms of an infection can be caused by:

• The infectious agent itself, or toxins it releases.
• The immune response to that infection, especially inflammatory responses

The duration of an infection can vary. An infection can be:

• Acute, meaning the infectious agent is soon removed, although the damage it causes may take longer to resolve.
• Chronic, meaning the infectious organism persists within our body long-term, avoiding immune clearance.

Some infections are chronic, but periodically reappear in an acute form.

Our immune system protects us from many infections. However, some infectious organisms have developed strategies to evade our immune defenses. These can include:

• Changing proteins on their surface (or the surface of an infected cell) to evade specific immune responses.
• Hiding within cells.
• Producing a dormant form that can re-awaken when host immunity is weakened.
• Residing in parts of the body that are poorly accessed by the immune system, such as the skin surface or brain.

Our researchers are discovering how particular infectious organisms evade immune detection. This is revealing new strategies for enhancing the immune response to clear the infection, and also new approaches to designing vaccines to prevent infection.

Two important ways to prevent contacting an infectious disease are:

• Avoiding exposure to the infectious agent, such as avoiding mosquito bites to prevent malaria, and washing hands to reduce the spread of influenza.
• Inducing a protective immune response, such as through vaccination, that prevents the infection establishing.

The smallpox virus was the first infection to be completely eliminated from humans worldwide, aided by a global vaccination program. Our researchers aspire to contribute to the elimination of other infections, particularly malaria.

The ideal treatments for infections kill the infectious agent without harming the body’s own cells. Many treatments target molecular differences between microbes and humans.

The broad classes of medicines used to treat infections are:

• Antivirals
• Antibiotics, to treat bacterial infections
• Antifungals
• Antiparasitics

Our researchers are investigating many new approaches to treating disease. An important focus is to identify molecules unique to an infectious agent that can be targeted by new medicines developed using medicinal chemistry.

Our researchers are also developing new approaches to treating infections, particularly chronic infections, by boosting the immune response to the infectious agent.

For some infectious diseases, treatments also involve reversing or resolving the damage caused by the infection. For example, people with gastrointestinal infections who are dehydrated are given additional fluids.

As infectious organisms proliferate, some acquire genetic changes. Occasionally these allow an organism to become resistant to a particular treatment. When that treatment is given, the resistant microbes can continue to grow in our bodies, replacing the treatment-sensitive organisms. Resistance is more likely to develop when people do not take a full course of treatment, such as an antibiotic course.

Over time a drug-resistant strain of a disease can become the predominant strain in the community. When more than one type of treatment for an infection is available, a strain of microbes resistant to one treatment may be sensitive to another.

Over time, multi-drug resistance can develop, rendering many treatments ineffective. Increasing rates of multi-drug resistance are limiting the options for treating many types of infection, including malaria and tuberculosis.

Our researchers aim to develop new treatments for infections using approaches that minimise the likelihood of resistance developing. By investigating the basic biology of infections, they are revealing how drug resistance occurs, and designing treatment strategies that are more difficult to evade.

Treatments that boost the immune system’s clearance of infections are another approach that may overcome problems posed by multidrug resistant infections.

Inflammation can have a variety of triggers including:

• tissue damage, such as a burn or cut
• clot formation by platelets
• the presence of a foreign substance
• microbial infection
• some forms of cell death.

Inflammation begins with innate immune cells, such as neutrophils, being alerted to the trigger. This may be because damaged tissue has released ‘alert’ signals, or because the immune cell has detected microbial molecules such as bacterial cell wall components.

When activated, innate immune cells can immediately release a variety of inflammatory substances. These substances trigger the features of inflammation in nearby tissue, protecting the site and attracting an influx of additional immune cells. Different immune cell types, and inflammatory mediators are detected in acute and chronic inflammation.

Inflammatory mediators are typically short-lived. This serves to limit the duration of an inflammatory response. As soon as the trigger is removed, inflammation will normally diminish, preventing tissue damage.

Our research into how cells die has revealed that many of the molecules contributing to cell death have dual roles in inflammation, or are closely related to molecules functioning in inflammatory pathways.

Some types of cell death trigger inflammation. This ensures that the abnormal death of cells alerts immune cells to a potentially dangerous situation.

Inflammation is an important component of the innate immune response, which is the body’s first line of defense against infection. Inflammatory mediators enhance the responses of immune cells to potential infections, by:

• increasing blood flow and movement of immune cells into the inflamed tissue
• stimulating immune cells, such as triggering macrophages to be more likely to engulf nearby substances
• stimulating production of new immune cells through the release of colony stimulating factors

Inflammation is important for the generation of protective immunological memory. This ensures that repeat exposures to a microbe are rapidly dealt with by established immune cells that recognise the infectious agent.

Most vaccines include substances that trigger inflammation. These contribute to better immune responses, and longer-lasting immune protection.

Excessive or ongoing inflammation can cause pain and tissue damage, and prevent the normal functioning of the body’s organs.

Short-term, acute inflammation can be responsible for many of the symptoms of infections. These symptoms, such as fever, tend to assist the immune clearance of infection. Excessive or misplaced acute inflammation can cause severe illness or death.

Chronic inflammation is also associated with many diseases. Approximately one in three Australians has a chronic inflammatory disease, such as rheumatoid arthritis. These diseases place a significant social and economic burden on the community.

Chronic inflammation is triggered by ongoing immune responses. These immune responses can be against:

• a chronic infection that is not cleared. Chronic inflammation to the hepatitis B virus contributes to liver damage
• the body’s own tissue, such as joint tissue in rheumatoid arthritis.

In some conditions, such as rheumatic fever, inflammation begins in response to an infection by Streptococcus bacteria, but is redirected later to heart tissue, causing damage.

In many inflammatory diseases, symptoms can be greatly reduced in the short term by appropriate treatment. These include:

• corticosteroids that reduce immune cell function
• ‘non-steroidal’ anti-inflammatory medications that interfere with key molecules or cells contributing to the symptoms of inflammation
• targeted therapies that specifically inhibit the molecules that underpin inflammation or immune cell function
• these are showing great promise in improving the outlook for people with inflammatory diseases.

Compressing, immobilising and cooling the inflamed area can also improve the symptoms of inflammation, but do not eliminate the underlying cause of the inflammation.

Our immune system has diverse strategies to prevent infection. The functions of the immune system can be broadly divided into:

Innate immune system: responds rapidly to microbes, but does not alter significantly on repeat exposure. Important aspects of this are:

• phagocytosis, or engulfment of microbes by cells.
• triggering inflammation in response to microbes or tissue damage.
• releasing substances that limit microbial invasion and recruit immune cells.

Adaptive immune system: develops ‘memory’ to microbes, allowing subsequent immune responses to the same microbe to be faster and larger. This immunological memory can last a lifetime.

Important aspects of adaptive immunity are:

• cells with receptors that recognise specific microbial proteins.
• antibodies, which are soluble proteins that can bind a specific microbial protein.

Innate immune responses typically occur more rapidly than adaptive responses. The innate and adaptive immune systems have many interactions, and can involve some of the same cells and molecules.

The immune system involves many different types of cells working together. Many of these are ‘white blood cells’ that develop from blood stem cells in the bone marrow.

Our researchers are contributing to the understanding of how immune cells develop and function. In doing this, they have revealed many sub-types of these cells.

Important immune cells include:

Phagocytes

These are innate immune cells that can engulf (phagocytose) microbes or other particles. They are important in triggering inflammation, and some can alert adaptive immune cells to an infection. Important phagocytes include:

• dendritic cells
• neutrophils
• basophils
• macrophages

Lymphocytes

These cells include adaptive and innate immune components, with many functions in controlling, stimulating and executing immune responses. Long-lived memory lymphocytes are the source of lifelong immunity to certain infections.

The broad types of lymphocytes are:

• B cells, adaptive immune cells that produce antibodies that specifically bind other proteins, such as on the surface of a microbe.
• T cells, adaptive immune cells that are stimulated by dendritic cells or other phagocytes to become activated against a particular microbe.
• Natural killer cells, which can have innate or adaptive roles in eliminating infections, and also killing cancer cells.

There are many factors released by immune cells that are important for immune reactions. These include:

• cytokines, hormone-like signalling proteins that allow cells to communicate with each other via cytokine receptors on the cell surface.
• antibodies, a type of protein released by B cells. Each antibody can bind a specific protein, called the ‘antigen’, with different antigens recognised by different antibodies. This identifies the antigen as ‘foreign’. The binding of an antibody to a microbe can hamper the microbe’s growth and survival.

For good health, both innate and adaptive immune responses need to:

• start and conclude rapidly to minimise damage to the body’s own cells.
• only occur in situations of genuine danger, in response to an invading microbe. Immune responses to harmless substances or the body’s own tissues causes disease.

The immune system contains many safeguards that regulate its functions. Many strategies are used to prevent harmful immune responses. This includes systems for destroying or silencing potentially harmful cells that could attack the body’s own tissues.

Usually the immune system can distinguish our own tissues from invading microbes, and respond appropriately, killing the microbes or infected cells but not harming uninfected or otherwise healthy cells. Defective control of the immune response, leading to misdirected, excessive or inadequate immune responses, underly many immune disorders.

Inflammatory disorders occur when the immune system causes excessive inflammation that damages the body. This may be triggered by an infection, such as in rheumatic fever or occur for no known reason, such as in inflammatory bowel disease.

Autoimmunity is a type of inflammatory disorder that occurs when the immune system mistakenly attacks the body’s own tissues. These disorders are caused by lymphocytes or antibodies reacting to the body’s own tissues.

Significant autoimmune diseases include:

• lupus
• type 1 diabetes
• rheumatoid arthritis
• coeliac disease

Allergy occurs when the immune system over-reacts to harmless factors in our diet or environment.

Immunodeficiency is a weakened immune system. This causes a person to be infected by microbes more easily than a healthy person.

Occasionally an immune cell develops changes in its genetic material that allow it to grow uncontrollably, and become long-lived. This can lead to cancers of the immune system, such as:

• leukaemia
• lymphoma
• myeloma

The normal functioning of our immune system is vital to our health. Immune cells can also be harnessed to treat disease, a field called immunotherapy. Examples of immunotherapy include:

• vaccines expose the immune system to substances that closely resemble a particular microbe, allowing the safe development of adaptive immunity. This protects the body from infection when the microbe is later encountered.
• targeted therapy can use antibodies to specifically bind to disease-causing molecules or cells. Many targeted therapies for cancer are being developed that bind to specific proteins on the cancer cell’s surface. Another strategy is to target immune cell communication molecules (such as cytokines) to enhance or inhibit the strength of response to cancer or autoimmune diseases.
• immunosuppression turns off the function of immune cells. Most immunosuppressive medications have widespread effects on immune cells, and can perturb protective as well as harmful immune responses.
• preventive vaccines switch off a harmful immune response by providing signals to the immune system that a substance is not harmful. Our researchers have developed potential preventive vaccines that are in clinical trials for coeliac disease and type 1 diabetes.

Most cell signalling relies on pathways of molecules signalling to each other to bring about a response.

A ‘signalling cascade’ describes one molecule signalling to several molecules, which then signal to several more, and so on. This results in an amplified and complex response to one initial signal.

Most external signals do not enter the cell themselves, but bind to the cell surface, usually via a protein called a receptor. These cell surface receptors often span the outer membrane of the cell.

Receptors are specific for one, or a few substances, called ‘ligands’. When the receptor is bound by its specific ligand, it changes shape in a way that is transmits the signal across the cell membrane – like turning a key in a lock moves the latch on the other side of the door.

Ligands are substances that specifically bind receptors. Many ligands are proteins, and fit precisely into specific receptors. Hormones and cytokines are common ligands for signalling between cells.

When a ligand binds a receptor, it triggers changes within the cell that influence other signalling molecules. Many signalling pathways involve proteins called kinases. Kinases can exist in ‘on’ and ‘off’ states of activation. In some cases, a binding of a ligand to a receptor will switch on (activate) a kinase.

When switched on, kinases attach a phosphate group onto other molecules, especially other proteins, changing how those proteins function. The proteins then have their own influences on other molecules.

Many signalling pathways influence which genes are switched on in a cell. This effect can be mediated via changes to transcription factors, proteins that bind to specific DNA sequences in the genome. A transcription factor binding to a gene begins the process of copying it into its RNA form, allowing production of a particular protein.

Many signalling pathways in humans involve specialised proteins. Cell death signalling pathways are an example of this. In apoptotic cell death, various cellular stresses or a specific ligand binding to a ‘death receptor’ trigger changes within the cell that activate caspases, proteins that demolish the cell in a tightly controlled way.

Cells in our body are constantly barraged with different signals from their environment. These signals may be short-lived and change rapidly. Cells need to be able to switch off signalling pathways as rapidly as they were switched on.

Proteins have evolved that act as feedback inhibitors and specifically terminate a cell signalling pathway. These proteins can switch off kinases or other signalling proteins, or initiate the destruction of proteins produced when the signalling pathway began.

The SOCS protein family was discovered by our researchers. These proteins specifically turn off many different types of signals. Our research has demonstrated that in the immune system SOCS proteins are especially important at restraining inflammatory signals. Without SOCS proteins, inflammatory signalling is prolonged and can cause tissue damage.

When cells do not respond appropriately to their environment, or do not work cooperatively with other cells, disease can result. Problems in cell signalling underlie many diseases.

Some examples of disrupted cell signalling in disease include:

• cancer cells have constant activation of signalling pathways instructing the cells to grow and divide. This often occurs because of changes (mutations) in receptors, protein kinases or transcription factors that keep the proteins an active state.
• some immunodeficiencies occur because immune cells lack the receptors for ligands that instruct immune cells to divide and develop, or lack the specific kinases that transmit these signals.
• many viruses, such as hepatitis B, produce proteins that interfere with the host cell’s signalling pathways in ways that suppress the immune system and enhance viral reproduction.

Cell signalling influences how cells behave in health and disease. Many medicines work by adjusting cell signalling pathways, often stifling a key signalling protein.

Some treatments for disease work by preventing a ligand binding to its receptor. Medications that block cytokine signalling between immune cells are in clinical use to treat inflammatory conditions such as rheumatoid arthritis.

Many new anti-cancer therapies target kinases that give cancer cells the signals to divide.

Our medicinal chemistry researchers are using three-dimensional structures of cell signalling proteins to develop small molecules that can specifically block the proteins’ function.