How Many Microbes Does It Take to Make You Sick?

The original version of this story appears in Quanta Magazine.

For a pathogen to make us sick, it has to overcome a lot of challenges. It must first enter the body, bypassing natural barriers such as skin, mucus, eyelashes and stomach acid. Then it must reproduce; Some bacteria and parasites can do this virtually anywhere in the body, while viruses and some other pathogens can only do this from within a cell. And during this time, it must ward off attacks from the body’s immune system.

So while we are constantly inundated with microbes, the number of microbes that enter our bodies is usually too small to overcome our defenses. (A small enough dose can even serve to remind our immune system of the existence of a pathogen, thereby boosting our antibody response to protect us against it.)

When enough pathogens manage to break down our defenses and begin to replicate, we get sick. It’s often just a numbers game. The more invaders you fight, the more likely you are to feel sick.

How many microbes need to enter the body before we start to feel sick?

This varies depending on the pathogen and is known as the “infectious dose” of a microbe. It usually takes several, but some microbes require an incredibly small number of organisms to trigger an infection. Take norovirus for example, the stomach bug known to spread whenever people are in close contact and touch the same surfaces, like on cruise ships. Its infectious dose can be as low as 18 individual viruses, making transmission incredibly easy. It is also very durable, even outside the body, so an infected person who oozes the virus can leave a large amount behind, enough to easily infect other people, even several days later.

What about the concept of “viral load”? Is this related?

These are similar ideas, but while infectious dose refers to the number of organisms that will cause infection, viral load is an active measure of infection: the number of organisms that replicate within the host . The terminology was first introduced to the general public as part of our understanding of HIV/AIDS, and its use increased after the start of the Covid pandemic.

How do researchers determine the infectious dose of a microbe?

This is still an inexact science. The baseline study, called a human challenge study, involves deliberately giving people a dose of the pathogen. Unfortunately, this approach is ethically difficult as this (obviously) carries a risk of serious illness and potential long-term complications.

Instead, researchers expose guinea pigs, rats, mice or ferrets, depending on the pathogen. But it can be difficult to directly extrapolate the animal dose to the human equivalent.

Additionally, the route of infection is important. Something that enters your bloodstream directly will likely require far fewer microbes to take hold than one that enters through your mouth or lungs, for example, since the bloodstream allows the pathogen to bypass many of the body’s defenses. ‘host. This is why, for example, the risk of HIV infection is much higher when it comes to a blood transfusion or a needle stick compared to a sexual route.

A third way to try to determine the infectious dose is to use observational studies, in which researchers infer the number by observing how long it takes for an exposed person (especially in families or other contact settings narrow) to get sick. As you might expect, this method is often complicated and inaccurate compared to the previous two methods.

Why are the infectious doses of some pathogens higher or lower than others?

We’re not sure. This could be due to the operation of an invader. The researchers have suggested that pathogens requiring direct contact with host cells tended to be more effective, so their infectious doses were quite low. But if bacteria attack host cells indirectly (e.g. by secreting proteins that damage host cells), then a larger dose of bacteria is needed to infect the host, because the host-altering secretions could be diluted in the time and space. This idea was supported in a 2012 study which also covered viruses, fungi and parasites. But we still need additional confirmations for a wider variety of microbes.

What do we know about the infectious dose of the virus causing Covid?

We’ve learned a lot in the four years since it first appeared, but much of it has come from animal models of infection and human observational studies. Most animal models require a high dose of virus: 10,000 to 1 million “plaque-forming units” (PFU), each unit sufficient to infect and kill a cell in tissue culture. Observational studies in humans, however, suggest that the infectious dose can be around 100 to 400 PFU on average, although again this method only offers a very rough guideline.

These studies suggest that one reason the virus is so easily transmissible is that it contains a relatively low infectious dose, similar to other respiratory viruses such as RSV and “cold” coronaviruses (and lower than the infectious dose of most influenza virus strains).