Immunity to extracellular and intracellular bacteria

Introduction

Immune response plays a vital role in protecting against infectious agents. It is the main impediment against the occurrence of disseminated infections that are usually associated with a high death rate. It is a well-known fact that for virtually all infectious diseases, the number of individuals exposed to infection is much higher than those actually presenting with a disease. This indicates that most persons are able to destroy these microorganisms and thus prevent the progression of an infection. By contrast immune deficiencies, whether of innate immunity (phagocytic cell dysfunction or complement deficiency) or adaptive immunity (antibody production deficiency or T-cell function deficiency), are strongly associated with increased susceptibility to infections.

 Immune response against bacteria

Bacteria are the microorganisms that most frequently cause infections in humans. The natural barriers against infection agents as well as innate and adaptive immunity participate in the protection mechanism against bacteria.

Ø  Via complement-mediated lysis

When bacteria, such as Neisseria meningitidis, invade the body, they are attacked by immune proteins called complement proteins. Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or the lectin pathway. The first steps of the classical complement pathway require the binding of antibodies to the surface of the target bacterium. The antibodies then become targets for one particular complement protein complex, known as C1 – C1 binds to the tail (known as Fc region) of the antibody. Once bound, C1 initiates a cascade of cleavage and reforming of complement complexes that ends in the binding of several complement proteins to the surface of the bacterium in the form of a membrane attack complex (MAC) (Figure 1), or can generate opsonins that label a bacterium for destruction. MAC can insert into the cell membrane of Gram-negative, but not Gram-positive, bacteria. There, it produces pores that allow the entry of membrane damaging molecules, such as lysozyme, and makes the bacterium susceptible to osmotic lysis. The alternative complement pathway does not require antibody to initiate the lysis of bacteria. In this pathway, complement proteins from a complex known as C3 directly bind to bacteria and activate downstream components in the complement cascade, once again ending in formation of MAC that causes lysis of the bacterium. During the lectin pathway, mannan-binding lectin (MBL) binds to proteins containing mannose residues that are found in some types of bacteria (such as Salmonella spp.). Once bound, MBL forms a complex with an enzyme called MBL-activated serine protease (MASP). In this form, this enzyme activates C3 convertase (by cleaving C2 and C4 complement components) that participates in forming MAC.

Ø  Via phagocytosis

Bacteria may also be killed by phagocytes. Immune proteins like acute phase proteins (like complement) and antibodies bind to the surface of bacteria by a process called opsonisation. Opsonised bacteria are, therefore, coated with molecules that phagocytic cells recognise and respond to. Activated phagocytes engulf and destroy opsonised bacteria by a process called phagocytosis. Complement C3b is a particularly important opsonisation protein for controlling bacterial infections by this mechanism. Opsonisation allows killing of Gram-positive bacteria (e.g. Staphylococcus spp.) that are resistant to killing by MAC.After bacteria are ingested by phagocytosis (Figure 2), they are killed by various processes that occur inside the cell, and broken into small fragments by enzymes. Phagocytes present the fragments on their surface via class II major histocompatibility (MHC class II) molecules.

Circulating helper T cells recognise these bacterial fragments and begin to produce proteins called cytokines. Two major groups of helper T cells are known as Th1 and Th2 cells. These cell types differ in the types of cytokine they secrete. Th1 cells predominantly produce interferon-g (IFN-g), which promotes cell-mediated immune mechanisms (see below). Th2 cells produce mostly interleukin-4 (IL-4), which promotes humoral immunity by activating B cells. B cells make antibodies that stick to extracellular bacteria and prevent their growth and survival.

Ø  Via cell-mediated immunity

Some bacteria engulfed during phagocytosis avoid the killing mechanisms of the phagocyte to survive inside cells. Macrophages are a common targets for intracellular bacteria (e.g. Salmonella spp.) that live inside cell compartments. These bacteria cannot be detected by complement or antibody but, instead, are eliminated using a cell-mediated response. Infected macrophages present bacterial peptides on their cell surface using MHC class II molecules. This mechanism is called antigen presentation. A helper T cell surveys MHC class II molecules with its T-cell receptor (TCR) to observe the peptides they hold. If a bacterial peptide is presented, the Th1 cell releases IFN-g. This cytokine stimulates killing mechanisms, (such as production of lysozyme) inside the infected macrophage to digest and destroy the invading bacterium. IFN-g also increases antigen presentation by cells, making the bacterium more visible to the immune system and more prone to attack.

Immune response against intracellular bacteria

Some intracellular bacteria like pathogenic or facultative are able to multiply within the phagocytes, so their elimination from the patients requires modified strategies.

Ø  Innate immunity to intracellular bacteria

Phagocytes and natural killer cells provide innate immunity to the intracellular bacteria. However some bacteria survive and multiply easily in the phagocytes, the phagocytes need to be stimulated by the secretions of these bacteria in order to clear the infection. The secretions from these bacteria are recognized by TLRs and cytoplasmic proteins of the NOD-like receptor (NLR) family so that they stimulate the phagocytes to degrade the invading bacteria. In addition to the intracellular bacteria, activated natural killer cells produce IFN-γ, which consecutively stimulates macrophages and cytokines. Although innate immunity provides protection from most of the bacteria but some intracellular bacteria like Listeria monocytogenes need cell mediated immunity in order to be eliminated from the body.

Ø  Adaptive immunity to intracellular bacteria

T cell-mediated immunity plays a significant role in providing protection against intracellular bacteria. CD4+ T-cells and CD8+ cytotoxic T lymphocytes are the two major forms of cell mediated immunity that participate in phagocytosis or killing of infected cells, respectively. Both the, CD4+ T-cells and CD8+ cytotoxic T lymphocytes work together to provide protection against the intracellular bacteria. Granulomatous Joint initiative of IITs and IISc – Funded by MHRD inflammation acts as a marker for most of the infections due to intracellular bacteria, which occurs because of T-cell and macrophage stimulation. Macrophage stimulation that occurs as an antigenic response towards intracellular microbes is sometimes able to cause tissue damage. The response shown by different patients towards the intracellular microbes decides the development of the disease and its consequence. One neat example of such type of response is shown by leprosy patients. Leprosy is a disorder caused by Mycobacterium leprae and it exists in two forms, the lepromatous and tuberculoid form. Lepromatous form is characterized by feeble cell-mediated immune response and high specific antibody titer while the tuberculoid form shows low specific antibody titer but very strong cell-mediated immune response. Although the reasons attributed to this type of response are still speculated and not yet verified, one of the factors that are given significance is regarding varied pattern of cytokine production and T-cell differentiation in patients.

Ø  Dodging of immune system by intracellular bacteria

Intracellular bacteria tend to dodge the immune system in many ways comprising evading into the cytosol or preventing phagolysosome fusion and by overpowering the reactive oxygen species by their microbicidal activity. These bacteria have the potential to cause chronic infections because they can survive the phagocyte mediated elimination and thrive for years in the body and may show reversion of the disease.

Immune response against extracellular bacteria

 Extracellular bacteria are those that multiply and reside outside the host cell. These bacteria mainly affect the cells in two ways. They either attack by causing inflammation and tissue damage or by producing toxins.

Ø  Innate immunity to extracellular bacteria

Innate immunity to extracellular bacteria essentially involves three processes.

·         Stimulation of phagocytes- Phagocytes takes the help of surface receptors and Fc receptors to identify extracellular bacteria and its opsonization with the help of antibodies, respectively. Most of these receptors are associated with promotion of phagocytic activity and microbicidal activity.

·          Induction of inflammatory response- Antigen presenting cells like dendritic cells in addition to phagocytes are stimulated by microbes and these cells secrete cytokines which are responsible for causing leukocyte infiltration at the site of inflammation.

·         Activation of complement system- Both gram positive and gram negative bacteria stimulate alternative pathway of complement system and mannose expressing bacteria stimulate lectin pathway of complement system by binding to mannose binding lectin.

Ø  Adaptive immunity to extracellular bacteria

The immunity that plays major role against extracellular bacteria is the humoral or antibody mediated immunity as it prevents the infection by neutralizing the toxins. Usually polysaccharide antigens are prototypic thymus-independent antigens and humoral immunity is the basic line of defense against polysaccharide-rich encapsulated bacteria. The antibodies in such cases defend the body by neutralization, opsonization, phagocytosis and stimulation of complement system. Extracellular bacteria also stimulate the production of CD4+ helper T cells which induces inflammation and phagocytic activity. Besides this, these antigens may cause some mutational disorders and also the affected individual may have reduced immune response towards microbial infections.

Ø  Immune evasion by extracellular bacteria

1.      Polysaccharide antigens or encapsulated bacteria are more lethal as compared to a strain devoid of capsule because they resist phagocytosis.

2.      Capsulated bacteria inhibit alternate pathway of complement system due to the presence of sialic acid.

3.      One more way of evading immune response by extracellular bacteria is due to the genetic edition of surface antigens. E.g. surface antigen of some specific bacteria is contained in their pili. Pili contain a protein antigen called “pilin” and this pilin undergoes gene variation. Pili are the structures of bacteria responsible for bacterial adhesion to host cells.

Conclusion

Bacterial pathogens are often associated with many health issues globally and are capable to cause diseases irrespective of host species involved. Although there are principal protective immune response mechanisms associated like HMI, CMI and many more which are capable of defending our system from these harmful invaders.

Probiotics

Introduction

Probiotics are live microorganisms that are intended to have health benefits when consumed, generally by improving or restoring the gut flora. Probiotics are considered generally safe to consume, but may cause bacteria-host interactions and unwanted side effects in rare cases. Probiotics are live bacteria good for digestive system.

Although people often think of bacteria and other microorganisms as harmful “germs,” many microorganisms help our bodies function properly. For example, bacteria that are normally present in our intestines help digest food, destroy disease-causing microorganisms, and produce vitamins. Large numbers of microorganisms live on and in our bodies. Many of the microorganisms in probiotic products are the same as or similar to microorganisms that naturally live in our bodies.

How Does Probiotic Work?

Researchers are trying to figure out exactly how probiotics work. Some of the ways they may keep you healthy:

• When someone loses "good" bacteria in their body, for example after they take antibiotics, probiotics can help replace them.
• Probiotics can help balance "good" and "bad" bacteria to keep body working the way it should.

What Does Probiotic Do?

Among other things, probiotics help send food through gut by affecting nerves that control gut movement. Researchers are still trying to figure out which are best for certain health problems. Some common conditions they treat are:

• Irritable bowel syndrome
• Inflammatory bowel disease (IBD)
• Infectious diarrhea (caused by viruses, bacteria, or parasites)
• Diarrhea caused by antibiotics

There is also some research that shows they're useful for problems in other parts of human body. For example:

• Skin conditions, like eczema
• Urinary and vaginal health
• Preventing allergies and colds

History of Probiotics

Probiotics have received renewed attention in the 21st century from product manufacturers, research studies, and consumers. The history of probiotics can be traced to the first use of cheese and fermented products, that were well known to the Greeks and Romans who recommended their consumption.

Élie Metchnikoff first suggested the possibility of colonizing the gut with beneficial bacteria in the early 20th century.

The original modern hypothesis of the positive role played by certain bacteria was first introduced by Russian scientist and Nobel laureate Élie Metchnikoff, who in 1907 suggested that it would be possible to modify the gut microbiota and to replace harmful microbes with useful microbes. Bifidobacteria were first isolated from a breast-fed infant by Henry Tissier, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis was later renamed to the genus Bifidobacterium. Tissier found that bifidobacteria are dominant in the gut microbiota of breast-fed babies and he observed clinical benefits from treating diarrhea in infants with bifidobacteria.

During an outbreak of shigellosis in 1917, German professor Alfred Nissle isolated a strain of Escherichia coli from the feces of a soldier who was not affected by the disease. Methods of treating infectious diseases were needed at that time when antibiotics were not yet available, and Nissle used the E. coli Nissle 1917 strain in acute gastrointestinal infectious salmonellosis and shigellosis.

In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine.

Contrasting antibiotics, probiotics were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989 Roy Fuller suggested a definition of probiotics that has been widely used: "A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." Fuller's definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.

The term "probiotic" originally referred to microorganisms that have effects on other microorganisms. The conception of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used againto describe tissue extracts that stimulated microbial growth. The term probiotics was taken up by Parker, who defined the concept as, "Organisms and substances that have a beneficial effect on the host animal by contributing to its intestinal microbial balance."

In the following decades, intestinal lactic acid bacterial species with alleged health beneficial properties were introduced as probiotics, including Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus johnsonii.

Types of Probiotics

Many types of bacteria are classified as probiotics. They all have different benefits, but most come from two groups. Ask your doctor about which might best help you.

• Lactobacillus may be the most common probiotic. It’s the one you’ll find in yogurt and other fermented foods. Different strains can help with diarrhea and may help with people who can’t digest lactose, the sugar in milk.
• Bifidobacterium can be found in some dairy products. It may help ease the symptoms of irritable bowel syndrome and some other conditions.
• Saccharomyces boulardii is a yeast found in probiotics. It appears to help fight diarrhea and other digestive problems.

How to Use Probiotics Safely

The FDA regulates probiotics like foods, not like medications. Unlike drug companies, makers of probiotic supplements don't have to show their products are safe or that they work.

In general, probiotic foods and supplements are thought to be safe for most people, though some people with immune system problems or other serious health conditions shouldn't take them.

In some cases, mild side effects might include an upset stomach, diarrhea, gas, and bloating for the first couple of days after you start taking them. They may also trigger allergic reactions. Stop taking them and talk to your doctor if you have problems.

Side effects of Probiotics

The manipulation of the gut microbiota is complex and may cause bacteria-host interactions. Though probiotics are considered safe, some have concerns about their safety in certain cases. Some people, such as those with immunodeficiency, short bowel syndrome, central venous catheters, cardiac valve disease and premature infants, may be at higher risk for adverse events.

In severely ill people with inflammatory bowel disease there is a risk of the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) as a consequence of bacteremia, which can cause adverse health consequences.

Rarely, consumption of probiotics by children with lowered immune system function or who are already critically ill may result in bacteremia or fungemia (i.e., bacteria or fungi in the blood), which can lead to sepsis, a potentially fatal disease.

It has been suggested that Lactobacillus contributes to obesity in humans, but no evidence of this relationship has been found

Effectiveness of Probiotics

 Researchers have studied probiotics to find out whether they might help prevent or treat a variety of health problems, including:

• Digestive disorders such as diarrhea caused by infections, antibiotic-associated diarrhea, irritable bowel syndrome, and inflammatory bowel disease
• Allergic disorders such as atopic dermatitis (eczema) and allergic rhinitis (hay fever)
• Tooth decay, periodontal disease, and other oral health problems
• Colic in infants
• Liver disease
• The common cold
• Prevention of necrotizing enterocolitis in very low birth weight infants.

There’s preliminary evidence that some probiotics are helpful in preventing diarrhea caused by infections and antibiotics and in improving symptoms of irritable bowel syndrome, but more needs to be learned. We still don’t know which probiotics are helpful and which are not.

We also don’t know how much of the probiotic people would have to take or who would most likely benefit from taking probiotics. Even for the conditions that have been studied the most, researchers are still working toward finding the answers to these questions.

Probiotics are not all alike. For example, if a specific kind of Lactobacillus helps prevent an illness, that doesn’t necessarily mean that another kind of Lactobacillus would have the same effect or that any of the Bifidobacterium probiotics would do the same thing.

Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking. The U.S. Food and Drug Administration (FDA) has not approved any probiotics for preventing or treating any health problem.

Some experts have cautioned that the rapid growth in marketing and use of probiotics may have outpaced scientific research for many of their proposed uses and benefits.

The dietary sources of Probiotics

Probiotics which are usually beneficial bacteria  provide all sorts of powerful benefits for human body and brain. They may improve digestive health, reduce depression and promote heart health. Some evidence suggests they may even give better-looking skin. Getting probiotics from supplements is popular, but you can also get them from fermented foods.

Here is a list of 11 probiotic foods that are super healthy. 

• Yogurt is one of the best sources of probiotics, which are friendly bacteria that can improve your health. It is made from milk that has been fermented by friendly bacteria, mainly lactic acid bacteria and bifidobacteria
•  Kefir is a fermented probiotic milk drink. It is made by adding kefir grains to cow's or goat's milk.
• Sauerkraut is finely shredded cabbage that has been fermented by lactic acid bacteria. 
• Tempeh is a fermented soybean product. It forms a firm patty whose flavor is described as nutty, earthy or similar to a mushroom
•  Kimchi is a fermented, spicy Korean side dish.
•  Miso is a Japanese seasoning. It is traditionally made by fermenting soybeans with salt and a type of fungus called koji. Kombucha is a fermented black or green tea drink. 
• Pickles (also known as gherkins) are cucumbers that have been pickled in a solution of salt and water. 
• Traditional Buttermilk actually refers to a range of fermented dairy drinks.  
•  Natto is another fermented soybean product, like tempeh and miso. It contains a bacterial strain called Bacillus subtilis.
• Although most types of cheese are fermented, it does not mean that all of them contain probiotics.

Global consumption of Probiotics

In 2015, the global retail market value for probiotics was US$41 billion, including sales of probiotic supplements, fermented milk products, and yogurt, which alone accounted for 75% of total consumption.

Innovation in probiotic products in 2015 was mainly from supplements, which produced US$4 billion and was projected to grow 37% globally by 2020. Consumption of yogurt products in China has increased by 20% per year since 2014.