Discusses chronic infectious diseases that may be helped by autophagy induction
Infections are diseases caused by invading organisms be they viruses, bacteria, protozoa (nucleated single-cell organisms – protists), or higher organisms such as worms or lice. Usually the course of an infection is short as the body mounts its defenses and eliminates the invader. Some invaders, however, can survive what the body throws at it and produce a so-called chronic or latent infection: chronic if disease symptoms persist, latent if they recur later. This usually involves the invader finding a refuge within the body where the body’s immune system cannot reach and from which counter-attacks can be mounted.
Some viruses such as those that cause chicken pox and other herpes conditions find refuge in the nucleus of the cell. They incorporate themselves into the DNA and wait for suitable conditions to again reproduce. This is how the chicken pox herpes virus can cause the disease condition known as shingles decades after its initial infection.
Other organisms find refuge in the body spaces outside the cell: tape worms for instance in the intestine or lice on hair follicles.
Some can directly invade and survive within the cytoplasm of the cell. Many, however, find refuge within the cell’s own vesicles. They enter either by their own mechanisms or by being endocytosed by phagocytes. Normally the vesicle they then inhabit would merge with lysosomes and the invader would be thereby destroyed. These invaders, however, prevent this ‘maturation’ process by producing substances that block or counter-act it. They are then safe and secure often within the very cell whose job is to destroy all invaders, the phagocyte
Protein cycling may be a therapeutic approach against all diseases of this class. Promoting autophagy repeatedly may cause the blockage produced by the invader to be overridden, allowing the invader’s vesicle to ‘mature’ to lysis. Or the autophageosome induced by protein cycling may itself engulf the invader’s vesicle. Either way, the invader is destroyed. Induced autophagy may or may not then be adequate in and of itself to entirely eliminate the invader from the body.
These organisms that hide in vesicles produce some of the most significant diseases that plague mankind including malaria, schistosomiasis, tuberculosis and even ulcers and may underlie diseases yet unknown and consequences of those diseases such as cancer, nephritis or arthritis. Suppression of such organisms may even account for the benefits documented for autophagy -promoting drugs and practices such as calorie restriction and ADCR. We shall now examine some of these diseases in detail from the perspective of autophagy promotion.
Malaria is caused by a protozoan called plasmodium that, despite having a nucleus, a mitochondrion and a plastid, is small enough to invade red blood cells and take up residence there. Proliferation in red blood cells produces an acute malaria that resolves as the spleen destroys the infected cells. Similar organisms cause schistosomiasis and trypanosomiasis, all of which are very significant chronic diseases in the tropics.
Two species of plasmodium, P. vivax and P. ovale, can produce a chronic or latent malaria by hiding inside of liver cells. Interestingly chloroquine, the traditional drug of choice against malaria, is an autophagy inhibitor. Red blood cells have no nuclei or mitochondria and do not perform autophagy. A plasmodium in a red blood cell would be untouched by autophagy promotors, though that would not be true for the plasmodia in liver cells. Perhaps the plasmodium in the red blood cell needs its own autophagy to survive nutrient restriction and its inhibition blocks its proliferation.
Chimpanzees can be infected with the Hepatitis B virus where up to 75% of liver cells contain visible virus particles that disappear as the chimpanzee fights off the disease. Cell destruction, however, is not seen in this process as would be expected if the immune system was clearing the particles66. Presumably then it is autophagy doing the clearing. Hepatitis B is sometimes chronic in humans perhaps because autophagy is inadequate in those cases.
The Dengue virus initially enters the cell by inducing endocytosis at the cell surface. The resulting single-membraned endosome containing the virus particle then fuses with the double-membraned autophageosome. The virus then recruits the cells machinery to produce substances that prevent lysosomes from merging with the autophageosome and destroying it and the virus it contains67 .
Tuberculosis is caused by a number of species of mycobacteria when the organism takes up residence, most often in vesicles in the macrophages of the lung. Usually the body can eliminate the infection, but, in many cases, it becomes chronic. Other immune cells cluster around the infected macrophages to produce the ‘tubercles’, the granules that give the disease its name. It has been found that autophagy helps eliminate the organism68. Leprosy is caused by a similar organism.
Lyme Disease and other tick-borne diseases
Lyme disease and its relatives are caused by infection with a species of corkscrew shaped spirochete bacterium called Borrelia. The organism assumes a globular form, the so-called cyst state, that can survive inside human cells and create a chronic disease often misdiagnosed as ALS, MS or another neurological disease.
Crohn’s Disease, Colitis and IBS
Though historically thought to be genetic conditions, recent evidence suggests that the common gut bacterium Eschericia coli may be the cause when it takes up residence in vesicles inside intestinal macrophages69 . Interestingly, a number of unrelated bacterial species share this capability by sharing a ring of DNA called a plasmid70 . This plasmid is separate from the main DNA ring of the bacterium and encodes a number of proteins required for invasion of human cells. In this way, the plasmid could be considered as a virus of the bacterium. Indeed many of the proteins it encodes are similar to the proteins of true bacterial viruses. Further the plasmid can sometimes be transmitted to ‘uninfected’ bacteria even across species. This bacterial ‘virus’ may then be true infectious agent responsible for these and perhaps many other diseases that vary only on the particular bacterial ‘host‘ species involved.
Ulcers are usually caused by a bacterium Helicobacter pylori that has figured out how to survive within the hostile acid environment of the stomach. Recent evidence shows that ulcers result when the bacterium takes up residence in vesicles inside the cells lining the stomach85 .