How Many Microbes Does It Take to Make You Sick?

The original version of this story appeared in Quanta Magazine.

For a pathogen to make us sick, it must overcome a lot. First it has to enter the body, bypassing natural barriers such as skin, mucus, cilia, and stomach acid. Then it needs to reproduce; some bacteria and parasites can do this virtually anywhere in the body, while viruses and some other pathogens can only do so from within a cell. And all the while, it must parry attacks from the body’s immune system.

So while we are constantly inundated by microbes, the number of microbes that enter our bodies is usually too low to get past our defenses. (A tiny enough dose may even serve to remind our immune system of a pathogen’s existence, boosting our antibody response to keep us protected against it.)

When enough pathogens do manage to breach our defenses and start to replicate, we get sick. Often this is just a numbers game. The more invaders you’re fighting off, the more likely you are to feel ill.

How Many Microbes Need to Enter the Body Before We Start to Feel Sick?

This varies by pathogen and is known as a microbe’s “infectious dose.” Usually it takes quite a few, but some microbes require an incredibly small number of organisms to start an infection. Take norovirus for example, the stomach bug notorious for spreading whenever people are in close contact and touch the same surfaces, such as on cruise ships. Its infectious dose can be as small as 18 individual viruses, making it incredibly easy to transmit. It is also very hardy even outside the body, so an infected person who’s oozing the virus may leave a large amount of it behind—enough to easily infect others, even several days later.

What About the Concept of “Viral Load”? Is That Related?

They’re similar ideas, but while infectious dose refers to how many organisms will lead to an infection, viral load is an active measurement of infection: the number of organisms that are replicating within the host. The terminology was first introduced to the general public as part of our understanding of HIV/AIDS, and it increased in use after the start of the Covid pandemic.

How Do Researchers Figure Out a Microbe’s Infectious Dose?

That’s still an inexact science. The gold-standard study, called a human challenge study, involves purposely giving people a dose of the pathogen. Unfortunately, this approach is ethically difficult since it (obviously) carries a risk of serious illness and potential long-term complications.

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

Additionally, the route of infection matters. Something that gets right into your bloodstream will likely require far fewer microbes to take hold than one that comes in through your mouth or lungs, for example, since the bloodstream allows the pathogen to bypass many host defenses. This is why, for example, the risk of HIV infection is much higher when it comes from a blood transfusion or needle stick versus a sexual route.

A third way of trying to figure out infectious dose is to use observational studies, where researchers deduce the number from seeing how long it takes for an exposed person (especially in families or other close-contact settings) to become sick. As you might suspect, this is often messy and inexact compared to the previous two methods.

Why Are the Infectious Doses of Some Pathogens Higher or Lower Than Those of Others?

We aren’t sure. It could be due to how an invader operates. Researchers have suggested that pathogens requiring direct contact with host cells tended to be more effective, so their infectious doses were fairly low. But if bacteria attack host cells indirectly (such as by secreting proteins that go on to harm host cells), then a larger dose of bacteria is necessary to infect the host, since the host-modifying secretions could be diluted by time and space. This idea was supported in a 2012 study that looked at viruses, fungi, and parasites as well. But we still need additional confirmation for a wider variety of microbes.

What Do We Know About the Infectious Dose for the Virus that Causes Covid?

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

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